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16 pages, 8040 KiB

Open AccessArticle

Design, Synthesis, Molecular Docking Study and Biological Evaluation of Novel γ-Carboline Derivatives of Latrepirdine (Dimebon) as Potent Anticancer Agents

by Ramakrishna Voggu, Arundhati Karmakar, Venkat Swamy Puli, V. Surendra Babu Damerla, Padma Mogili, P. Amaladass, Sridhar Chidara, Kalyan Kumar Pasunooti and Sarika Gupta

Molecules 2023, 28(13), 4965; https://doi.org/10.3390/molecules28134965 - 24 Jun 2023

Cited by 4 | Viewed by 1825

Abstract

A series of novel γ-Carboline derivatives were designed and synthesized using the Suzuki coupling reaction to identify the leads for the activity against cancer. Interestingly, these compounds were tested for their anticancer activity against the cell lines, particularly human cancer cell lines MCF7 [...] Read more.

A series of novel γ-Carboline derivatives were designed and synthesized using the Suzuki coupling reaction to identify the leads for the activity against cancer. Interestingly, these compounds were tested for their anticancer activity against the cell lines, particularly human cancer cell lines MCF7 (breast), A549 (lung), SiHa (cervix), and Colo-205 (colon). Most of the γ-Carboline derivatives showed potent inhibitory activity in four cancer cell lines, according to in vitro anticancer activity screening. Two compounds, specifically LP-14 and LP-15, showed superior activity in cancer cell lines among the γ-Carboline derivatives from LP-1 to LP-16. Additionally, the compound LP-14, LP-15 and Etoposide carried out molecular docking studies on human topoisomerase II beta in complex with DNA and Etoposide (PDB ID: 3QX3). The docking studies’ results showed that the derivative LP-15 was strongly bound with the receptor amino acid residues, including Glu477 and DC8 compared with the marked drug Etoposide. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 4744 KiB

Open AccessArticle

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers

by Yasser M. Zohny, Samir M. Awad, Maha A. Rabie and Omar Awad Alsaidan

Molecules 2023, 28(12), 4869; https://doi.org/10.3390/molecules28124869 - 20 Jun 2023

Cited by 6 | Viewed by 2162

Abstract

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate [...] Read more.

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a–c in acid medium (HCl) yielding pyrimidines 4a–c, which in turn were hydrolyzed to carboxylic acid derivatives 5a–c which were chlorinated by SOCl₂ to give acyl chlorides 6a–c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a–c, 8a–c, and 9a–c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, ¹HNMR, ¹³CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC₅₀ measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure–activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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13 pages, 2288 KiB

Open AccessArticle

Anticancer Properties of 3-Dietoxyphosphorylfuroquinoline-4,9-dione

by Joanna Drogosz-Stachowicz, Katarzyna Gach-Janczak, Marek Mirowski, Jacek Pietrzak, Tomasz Janecki and Anna Janecka

Molecules 2023, 28(7), 3128; https://doi.org/10.3390/molecules28073128 - 31 Mar 2023

Viewed by 1736

Abstract

Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2-g]quinolin-3-yl)phosphonate (AJ-418) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of [...] Read more.

Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2-g]quinolin-3-yl)phosphonate (AJ-418) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of its strong antiproliferative activity against MCF-7 and MDA-MB-231 cells and 4-5-fold lower cytotoxicity towards healthy MCF-10A cells. The morphology of MCF-7 and MDA-MB-231 cancer cells treated with AJ-418 changed drastically, while non-tumorigenic MCF-10A cells remained unaffected. In MCF-7 cells, after 24 h incubation, the increased number of apoptotic cells coincided with a decrease in proliferation and cell viability. The 24 h treatment of MDA-MB-231 cells with the tested compound reduced their cell viability and proliferation rate; however, a significant pro-apoptotic effect was visible only after longer incubation times (48 h and 72 h). Then, the maximum tolerated dose (MTD) of compound AJ-418 in C3H mice after subcutaneous administration was determined to be 160 mg/kg, showing that this analog was well tolerated and can be further evaluated to assess its potential therapeutic effect in tumor-bearing mice. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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32 pages, 9047 KiB

Open AccessArticle

New Bicyclic Pyridine-Based Hybrids Linked to the 1,2,3-Triazole Unit: Synthesis via Click Reaction and Evaluation of Neurotropic Activity and Molecular Docking

by Samvel N. Sirakanyan, Domenico Spinelli, Anthi Petrou, Athina Geronikaki, Victor G. Kartsev, Elmira K. Hakobyan, Hasmik A. Yegoryan, Luca Zuppiroli, Riccardo Zuppiroli, Armen G. Ayvazyan, Ruzanna G. Paronikyan, Tatevik A. Arakelyan and Anush A. Hovakimyan

Molecules 2023, 28(3), 921; https://doi.org/10.3390/molecules28030921 - 17 Jan 2023

Cited by 3 | Viewed by 1570

Abstract

The synthesis of new original bicyclic pyridine-based hybrids linked to the 1,2,3-triazole unit was described via a click reaction. The anticonvulsant activity and some psychotropic properties of the new compounds were evaluated. The biological assays demonstrated that some of the studied compounds showed [...] Read more.

The synthesis of new original bicyclic pyridine-based hybrids linked to the 1,2,3-triazole unit was described via a click reaction. The anticonvulsant activity and some psychotropic properties of the new compounds were evaluated. The biological assays demonstrated that some of the studied compounds showed high anticonvulsant and psychotropic properties. The five most active compounds (7a, d, g, j, and m) contain a pyrano [3,4-c]pyridine cycle with a methyl group in the pyridine ring in their structures. Furthermore, molecular docking studies were performed, and their results are in agreement with experimental data. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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14 pages, 1958 KiB

Open AccessArticle

Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies

by Michelyne Haroun, Anthi Petrou, Christophe Tratrat, Aggeliki Kolokotroni, Maria Fesatidou, Panagiotis Zagaliotis, Antonis Gavalas, Katharigatta N. Venugopala, Nagaraja Sreeharsha, Anroop B. Nair, Heba Sadek Elsewedy and Athina Geronikaki

Molecules 2022, 27(23), 8137; https://doi.org/10.3390/molecules27238137 - 22 Nov 2022

Cited by 4 | Viewed by 1968

Abstract

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as [...] Read more.

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure–activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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15 pages, 1834 KiB

Open AccessArticle

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

by Georgios Papagiouvannis, Panagiotis Theodosis-Nobelos and Eleni A. Rekka

Molecules 2022, 27(20), 6984; https://doi.org/10.3390/molecules27206984 - 17 Oct 2022

Cited by 4 | Viewed by 1877

Abstract

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the [...] Read more.

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC₅₀ as low as 20 μΜ), as oxidative protein glycation inhibitors (inhibition up to 57%), and act as DPPH reducing agents. Moreover, our compounds are moderate LOX inhibitors (up to 33% at 100 μΜ) and could reduce rat paw edema induced by carrageenan by up to 61%. Finally, some of them possessed inhibitory activity against acetylcholinesterase (IC₅₀ as low as to 47 μΜ). Our results indicate that our compounds could have the potentiality for further optimization as multi-targeting agents directed against AD. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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11 pages, 873 KiB

Open AccessArticle

New Thiazole Acetic Acid Derivatives: A Study to Screen Cardiovascular Activity Using Isolated Rat Hearts and Blood Vessels

by P. Raghunatha, Mohammed Naseeruddin Inamdar, Syed Mohammed Basheeruddin Asdaq, Mansour Almuqbil, Abdullah R. Alzahrani, Saleh I. Alaqel, Mehnaz Kamal, Firas Hamdan Alsubaie, Walaa F. Alsanie, Abdulhakeem S. Alamri, Syed Imam Rabbani, Mahesh Attimarad, S. Mohan and Majid Alhomrani

Molecules 2022, 27(19), 6138; https://doi.org/10.3390/molecules27196138 - 20 Sep 2022

Cited by 2 | Viewed by 1719

Abstract

Cardiovascular diseases are one of the major causes of mortalities worldwide. In the present research, new synthetic derivatives of thiazole were studied using isolated hearts and blood vessels of rats. The heart and thoracic aorta were tested with six new synthesized thiazole acetic [...] Read more.

Cardiovascular diseases are one of the major causes of mortalities worldwide. In the present research, new synthetic derivatives of thiazole were studied using isolated hearts and blood vessels of rats. The heart and thoracic aorta were tested with six new synthesized thiazole acetic acid derivatives (SMVA-10, SMVA-35, SMVA-40, SMVA-41, SMVA-42 and SMVA-60), and the data obtained were statistically analyzed and compared. Isolated rat hearts were used to record the changes in developed tension and heart rate, while thoracic aortas were used to measure the contractile response, before and after treatments. Analysis of the results indicated a significant (p < 0.01) increase in developed tension with the addition of SMVA-35, SMVA-40, SMVA-41 and SMVA-42, which was augmented in the presence of adrenaline without affecting the heart rate. On the other hand, acetylcholine significantly decreased the developed tension, which was significantly reversed (p < 0.01) in the presence of compounds (SMVA-35 and SMVA-60). However, in the presence of SMVA-35 and SMVA-40, acetylcholine-induced bradycardia was significantly (p < 0.01) reduced. Furthermore, only SMVA-42 induced a dose-dependent contractile response in the isolated blood vessel, which was abolished in the presence of prazosin. Therefore, it can be concluded that some of the new synthesized thiazole derivatives exhibited promising results by raising the developed tension without changing the heart rate or blood vessel function, which could be helpful in failing heart conditions. However, more research is required to fully comprehend the function, mechanism and effectiveness of the compounds. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 6529 KiB

Open AccessArticle

Antimicrobial and Cytotoxic Activity of Novel Imidazolium-Based Ionic Liquids

by Łukasz Pałkowski, Maciej Karolak, Andrzej Skrzypczak, Marta Wojcieszak, Filip Walkiewicz, Jonasz Podemski, Karol Jaroch, Barbara Bojko, Katarzyna Materna and Jerzy Krysiński

Molecules 2022, 27(6), 1974; https://doi.org/10.3390/molecules27061974 - 18 Mar 2022

Cited by 14 | Viewed by 2723

Abstract

In this study, a series of 10 novel 1-methyl-3-octyloxymethylimidazolium derivatives carrying various anionic moieties (4-hydroxybenzenesulfonate, benzenesulfonate, carvacroloxyacetate, chloride, formate, propionate, thymoloxyacetate, vanillinoxyacetate, eugenoloxyacetate and trimethylacetate) were synthesized. Compounds were tested for their antimicrobial activity against six microbe strains (Staph-ylococcus aureus, Pseudomonas aeruginosa, Klebsiella [...] Read more.

In this study, a series of 10 novel 1-methyl-3-octyloxymethylimidazolium derivatives carrying various anionic moieties (4-hydroxybenzenesulfonate, benzenesulfonate, carvacroloxyacetate, chloride, formate, propionate, thymoloxyacetate, vanillinoxyacetate, eugenoloxyacetate and trimethylacetate) were synthesized. Compounds were tested for their antimicrobial activity against six microbe strains (Staph-ylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, and Candida albicans), cytotoxic activity against the mouse melanoma cell line (B16 F10), and surface active properties. All synthesized compounds exhibited antimicrobial activity (expressed as minimum inhibitory concentration; in range of 0.10–27.82 mM/L), especially against Gram-positive bacteria and fungi. In addition, all compounds demonstrated cytotoxicity on B16 F10 cells (IC50 values 0.0101–0.0197 mM/L). Surface properties defined as CMC values, ranged from 0.72 to 32.35 mmol L-1. The obtained results provide an insight into the promising activity of a novel group of quaternary imidazolium derivatives having ionic liquid properties. The most potent compounds, containing a thymoloxyacetate and eugenoloxyacetate moiety, could be candidates for new antimicrobial agents or surfactants. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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25 pages, 4595 KiB

Open AccessArticle

Thiazolidin-4-Ones as Potential Antimicrobial Agents: Experimental and In Silico Evaluation

by Christophe Tratrat, Anthi Petrou, Athina Geronikaki, Marija Ivanov, Marina Kostić, Marina Soković, Ioannis S. Vizirianakis, Nikoleta F. Theodoroula and Michelyne Haroun

Molecules 2022, 27(6), 1930; https://doi.org/10.3390/molecules27061930 - 16 Mar 2022

Cited by 26 | Viewed by 2931

Abstract

Herein, we report computational and experimental evaluations of the antimicrobial activity of twenty one 2,3-diaryl-thiazolidin-4-ones. All synthesized compounds exhibited an antibacterial activity against six Gram-positive and Gram-negative bacteria to different extents. Thus, the MIC was in the range of 0.008–0.24 mg/mL, while the [...] Read more.

Herein, we report computational and experimental evaluations of the antimicrobial activity of twenty one 2,3-diaryl-thiazolidin-4-ones. All synthesized compounds exhibited an antibacterial activity against six Gram-positive and Gram-negative bacteria to different extents. Thus, the MIC was in the range of 0.008–0.24 mg/mL, while the MBC was 0.0016–0.48 mg/mL. The most sensitive bacterium was S. Typhimurium, whereas S. aureus was the most resistant. The best antibacterial activity was observed for compound 5 (MIC at 0.008–0.06 mg/mL). The three most active compounds 5, 8, and 15, as well as compound 6, which were evaluated against three resistant strains, MRSA, P. aeruginosa, and E. coli, were more potent against all bacterial strains used than ampicillin. The antifungal activity of some compounds exceeded or were equipotent with those of the reference antifungal agents bifonazole and ketoconazole. The best activity was expressed by compound 5. All compounds exhibited moderate to good drug-likeness scores ranging from −0.39 to 0.39. The docking studies indicated a probable involvement of E. coli Mur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds. Finally, the assessment of cellular cytotoxicity of the compounds in normal human MRC-5 cells revealed that the compounds were not toxic. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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8 pages, 2012 KiB

Open AccessCommunication

Synthesis and Biological Evaluation of Amidinourea Derivatives against Herpes Simplex Viruses

by Anita Toscani, Rossana Denaro, Sergio Fernando Castillo Pacheco, Matteo Biolatti, Silvia Anselmi, Valentina Dell’Oste and Daniele Castagnolo

Molecules 2021, 26(16), 4927; https://doi.org/10.3390/molecules26164927 - 14 Aug 2021

Cited by 7 | Viewed by 2816

Abstract

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of [...] Read more.

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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13 pages, 1030 KiB

Open AccessArticle

Synthesis, Antibacterial and Antifungal Activity of New 3-Aryl-5H-pyrrolo[1,2-a]imidazole and 5H-Imidazo[1,2-a]azepine Quaternary Salts

by Sergii Demchenko, Roman Lesyk, Oleh Yadlovskyi, Johannes Zuegg, Alysha G. Elliott, Iryna Drapak, Yuliia Fedchenkova, Zinaida Suvorova and Anatolii Demchenko

Molecules 2021, 26(14), 4253; https://doi.org/10.3390/molecules26144253 - 13 Jul 2021

Cited by 13 | Viewed by 3114

Abstract

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All [...] Read more.

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD₅₀ > 2000 mg/kg). Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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25 pages, 7920 KiB

Open AccessArticle

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation

by Michelyne Haroun, Christophe Tratrat, Anthi Petrou, Athina Geronikaki, Marija Ivanov, Ana Ćirić, Marina Soković, Sreeharsha Nagaraja, Katharigatta Narayanaswamy Venugopala, Anroop Balachandran Nair, Heba S. Elsewedy and Hafedh Kochkar

Molecules 2021, 26(13), 4061; https://doi.org/10.3390/molecules26134061 - 2 Jul 2021

Cited by 14 | Viewed by 2647

Abstract

Background: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance [...] Read more.

Background: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance of microbes to existing drugs creates the need for the development of new effective antimicrobial agents. In an attempt to improve the antibacterial activity of previously synthesized compounds modifications to their structures were performed. Methods: Nineteen thiazolidinone derivatives with 6-Cl, 4-OMe, 6-CN, 6-adamantan, 4-Me, 6-adamantan substituents at benzothiazole ring were synthesized and evaluated against panel of four bacterial strains S. aureus, L. monocytogenes, E. coli and S. typhimirium and three resistant strains MRSA, E. coli and P. aeruginosa in order to improve activity of previously evaluated 6-OCF₃-benzothiazole-based thiazolidinones. The evaluation of minimum inhibitory and minimum bactericidal concentration was determined by microdilution method. As reference compounds ampicillin and streptomycin were used. Results: All compounds showed antibacterial activity with MIC in range of 0.12–0.75 mg/mL and MBC at 0.25–>1.00 mg/mL The most active compound among all tested appeared to be compound 18, with MIC at 0.10 mg/mL and MBC at 0.12 mg/mL against P. aeruginosa. as well as against resistant strain P. aeruginosa with MIC at 0.06 mg/mL and MBC at 0.12 mg/mL almost equipotent with streptomycin and better than ampicillin. Docking studies predicted that the inhibition of LD-carboxypeptidase is probably the possible mechanism of antibacterial activity of tested compounds. Conclusion: The best improvement of antibacterial activity after modifications was achieved by replacement of 6-OCF₃ substituent in benzothiazole moiety by 6-Cl against S. aureus, MRSA and resistant strain of E. coli by 2.5 folds, while against L. monocytogenes and S. typhimirium from 4 to 5 folds. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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17 pages, 3746 KiB

Open AccessArticle

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

by Giovanni Petrillo, Cinzia Tavani, Lara Bianchi, Alice Benzi, Maria Maddalena Cavalluzzi, Lara Salvagno, Laura Quintieri, Annalisa De Palma, Leonardo Caputo, Antonio Rosato and Giovanni Lentini

Molecules 2021, 26(13), 3891; https://doi.org/10.3390/molecules26133891 - 25 Jun 2021

Cited by 4 | Viewed by 2235

Abstract

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of [...] Read more.

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1–2 μg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 μM, MIC: 8.6 μM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure–activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 1193 KiB

Open AccessArticle

Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

by Rita Meleddu, Angela Corona, Simona Distinto, Filippo Cottiglia, Serenella Deplano, Lisa Sequeira, Daniela Secci, Alessia Onali, Erica Sanna, Francesca Esposito, Italo Cirone, Francesco Ortuso, Stefano Alcaro, Enzo Tramontano, Péter Mátyus and Elias Maccioni

Molecules 2021, 26(13), 3821; https://doi.org/10.3390/molecules26133821 - 23 Jun 2021

Cited by 4 | Viewed by 2229

Abstract

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, [...] Read more.

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC₅₀ = 4.5 mM)- and RDDP (IC₅₀ = 8.0 mM) HIV RT-associated functions. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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25 pages, 3202 KiB

Open AccessArticle

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines, Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

by Samvel N. Sirakanyan, Domenico Spinelli, Athina Geronikaki, Victor Kartsev, Elmira K. Hakobyan, Anthi Petrou, Ruzanna G. Paronikyan, Ivetta M. Nazaryan, Hasmik H. Akopyan and Anush A. Hovakimyan

Molecules 2021, 26(11), 3320; https://doi.org/10.3390/molecules26113320 - 1 Jun 2021

Cited by 10 | Viewed by 3110

Abstract

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to [...] Read more.

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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12 pages, 685 KiB

Open AccessArticle

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities

by Lamya H. Al-Wahaibi, Ahmed A. B. Mohamed, Samar S. Tawfik, Hanan M. Hassan and Ali A. El-Emam

Molecules 2021, 26(8), 2110; https://doi.org/10.3390/molecules26082110 - 7 Apr 2021

Cited by 30 | Viewed by 3896

Abstract

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, [...] Read more.

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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12 pages, 2691 KiB

Open AccessFeature PaperArticle

New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents

by Christophe Tratrat, Michelyne Haroun, Aliki Paparisva, Charalmpos Kamoutsis, Anthi Petrou, Antonis Gavalas, Phaedra Eleftheriou, Athina Geronikaki, Katharigatta N. Venugopala, Hafedh Kochkar and Anroop B. Nair

Molecules 2021, 26(3), 659; https://doi.org/10.3390/molecules26030659 - 27 Jan 2021

Cited by 18 | Viewed by 3207

Abstract

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs [...] Read more.

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 927 KiB

Open AccessArticle

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer’s Disease Potential

by Alisa A. Nevskaya, Lada V. Anikina, Rosa Purgatorio, Marco Catto, Orazio Nicolotti, Modesto de Candia, Leonardo Pisani, Tatiana N. Borisova, Almira R. Miftyakhova, Aleksey V. Varlamov, Elena Yu. Nevskaya, Roman S. Borisov, Leonid G. Voskressensky and Cosimo D. Altomare

Molecules 2021, 26(2), 359; https://doi.org/10.3390/molecules26020359 - 12 Jan 2021

Cited by 10 | Viewed by 2927

Abstract

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino [...] Read more.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer’s disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with K_i in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC₅₀) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-amyloid (Aβ)_1–40 aggregation (IC₅₀ = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 1185 KiB

Open AccessArticle

Novel 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines: Synthesis and Biological Activity

by Kinga Paruch, Łukasz Popiołek, Anna Biernasiuk, Anna Hordyjewska, Anna Malm and Monika Wujec

Molecules 2020, 25(24), 5844; https://doi.org/10.3390/molecules25245844 - 10 Dec 2020

Cited by 6 | Viewed by 2454

Abstract

The aim of our study was the two-stage synthesis of 1,3,4-oxadiazole derivatives. The first step was the synthesis of hydrazide–hydrazones from 3-methyl-4-nitrobenzhydrazide and the corresponding substituted aromatic aldehydes. Then, the synthesized hydrazide–hydrazones were cyclized with acetic anhydride to obtain new 3-acetyl-2,3-disubstituted-1,3,4-oxadiazolines. All of [...] Read more.

The aim of our study was the two-stage synthesis of 1,3,4-oxadiazole derivatives. The first step was the synthesis of hydrazide–hydrazones from 3-methyl-4-nitrobenzhydrazide and the corresponding substituted aromatic aldehydes. Then, the synthesized hydrazide–hydrazones were cyclized with acetic anhydride to obtain new 3-acetyl-2,3-disubstituted-1,3,4-oxadiazolines. All of obtained compounds were tested in in vitro assays to establish their potential antimicrobial activity and cytotoxicity. Our results indicated that few of the newly synthesized compounds had some antimicrobial activity, mainly compounds 20 and 37 towards all used reference bacterial strains (except Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa) and fungi. These substances showed a strong or powerful bactericidal effect, especially against Staphylococcus spp. belonging to Gram-positive bacteria. Compound 37 was active against Staphylococcus epidermidis at minimal inhibitory concentration (MIC) = 0.48 µg/mL and was characterized by low cytotoxicity. This compound possessed quinolin-4-yl substituent in the second position of 1,3,4-oxadiazole ring and 3-methyl-4-nitrophenyl in position 5. High effectiveness and safety of these derivatives make them promising candidates as antimicrobial agents. Whereas the compound 20 with the 5-iodofurane substituent in position 2 of the 1,3,4-oxadiazole ring showed the greatest activity against S. epidermidis at MIC = 1.95 µg/mL. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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13 pages, 1694 KiB

Open AccessArticle

Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists

by Samo Guzelj and Žiga Jakopin

Molecules 2020, 25(22), 5228; https://doi.org/10.3390/molecules25225228 - 10 Nov 2020

Cited by 4 | Viewed by 2865

Abstract

The dipeptide d-Glu-meso-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The meso-diaminopimelic acid (meso-DAP) moiety is known to be very stringent in terms of the allowed [...] Read more.

The dipeptide d-Glu-meso-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The meso-diaminopimelic acid (meso-DAP) moiety is known to be very stringent in terms of the allowed structural modifications which still retain the NOD1 activity. The aim of our study was to further explore the chemical space around the meso-DAP portion and provide a deeper understanding of the structural features required for NOD1 agonism. In order to achieve the rigidization of the terminal amine functionality of meso-DAP, isoxazoline and pyridine heterocycles were introduced into its side-chain. Further, we incorporated the obtained meso-DAP mimetics into the structure of iE-DAP. Collectively, nine innovative iE-DAP derivatives additionally equipped with lauroyl or didodecyl moieties at the α-amino group of d-Glu have been prepared and examined for their NOD1 activating capacity. Overall, the results obtained indicate that constraining the terminal amino group of meso-DAP abrogates the compounds’ ability to activate NOD1, since only compound 6b retained noteworthy NOD1 agonistic activity, and underpin the stringent nature of this amino acid with regard to the allowed structural modifications. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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Review

Jump to: Research

28 pages, 19798 KiB

Open AccessReview

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency

by Yasser M. Zohny, Samir M. Awad, Maha A. Rabie and Omar A. Al-Saidan

Molecules 2023, 28(2), 784; https://doi.org/10.3390/molecules28020784 - 12 Jan 2023

Cited by 7 | Viewed by 4551

Abstract

Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ [...] Read more.

Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure–activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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15 pages, 5861 KiB

Open AccessReview

Sulfonamides with Heterocyclic Periphery as Antiviral Agents

by Mikhail Yu. Moskalik

Molecules 2023, 28(1), 51; https://doi.org/10.3390/molecules28010051 - 21 Dec 2022

Cited by 23 | Viewed by 3229

Abstract

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a “second wind”, due to the increase in the synthetic capabilities of organic chemistry [...] Read more.

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a “second wind”, due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum—along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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16 pages, 2946 KiB

Open AccessReview

Carbazole Derivatives as Potential Antimicrobial Agents

by Siddappa A. Patil, Shivaputra A. Patil, Ever A. Ble-González, Stephen R. Isbel, Sydney M. Hampton and Alejandro Bugarin

Molecules 2022, 27(19), 6575; https://doi.org/10.3390/molecules27196575 - 4 Oct 2022

Cited by 29 | Viewed by 3353

Abstract

Microbial infection is a leading cause of death worldwide, resulting in around 1.2 million deaths annually. Due to this, medicinal chemists are continuously searching for new or improved alternatives to combat microbial infections. Among many nitrogen-containing heterocycles, carbazole derivatives have shown significant biological [...] Read more.

Microbial infection is a leading cause of death worldwide, resulting in around 1.2 million deaths annually. Due to this, medicinal chemists are continuously searching for new or improved alternatives to combat microbial infections. Among many nitrogen-containing heterocycles, carbazole derivatives have shown significant biological activities, of which its antimicrobial and antifungal activities are the most studied. In this review, miscellaneous carbazole derivatives and their antimicrobial activity are discussed (articles published from 1999 to 2022). Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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30 pages, 2417 KiB

Open AccessReview

Comprehensive Review on Medicinal Applications of Coumarin-Derived Imine–Metal Complexes

by Siddappa A. Patil, Vishal Kandathil, Anjali Sobha, Sasidhar B. Somappa, Max R. Feldman, Alejandro Bugarin and Shivaputra A. Patil

Molecules 2022, 27(16), 5220; https://doi.org/10.3390/molecules27165220 - 16 Aug 2022

Cited by 18 | Viewed by 3593

Abstract

Coumarins are fused six-membered oxygen-containing benzoheterocycles that join two synthetically useful rings: α-pyrone and benzene. A survey of the literature shows that coumarins and their metal complexes have received great interest from synthetic chemists, medicinal scientists, and pharmacists due to their wide spectrum [...] Read more.

Coumarins are fused six-membered oxygen-containing benzoheterocycles that join two synthetically useful rings: α-pyrone and benzene. A survey of the literature shows that coumarins and their metal complexes have received great interest from synthetic chemists, medicinal scientists, and pharmacists due to their wide spectrum of biological applications. For instance, coumarin and its derivatives have been used as precursors to prepare a large variety of medicinal agents. Likewise, coumarin-derived imine–metal complexes have been found to display a variety of therapeutic applications, such as antibacterial, antifungal, anticancer, antioxidant, anthelmintic, pesticidal, and nematocidal activities. This review highlights the current synthetic methodologies and known bioactivities of coumarin-derived imine–metal complexes that make this molecule a more attractive scaffold for the discovery of newer drugs. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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33 pages, 11630 KiB

Open AccessReview

Triflamides and Triflimides: Synthesis and Applications

by Mikhail Y. Moskalik and Vera V. Astakhova

Molecules 2022, 27(16), 5201; https://doi.org/10.3390/molecules27165201 - 15 Aug 2022

Cited by 5 | Viewed by 4407

Abstract

Among the variety of sulfonamides, triflamides (CF₃SO₂NHR, TfNHR) occupy a special position in organic chemistry. Triflamides are widely used as reagents, efficient catalysts or additives in numerous reactions. The reasons for the widespread use of these compounds are their [...] Read more.

Among the variety of sulfonamides, triflamides (CF₃SO₂NHR, TfNHR) occupy a special position in organic chemistry. Triflamides are widely used as reagents, efficient catalysts or additives in numerous reactions. The reasons for the widespread use of these compounds are their high NH-acidity, lipophilicity, catalytic activity and specific chemical properties. Their strong electron-withdrawing properties and low nucleophilicity, combined with their high NH-acidity, makes it possible to use triflamides in a vast variety of organic reactions. This review is devoted to the synthesis and use of N-trifluoromethanesulfonyl derivatives in organic chemistry, medicine, biochemistry, catalysis and agriculture. Part of the work is a review of areas and examples of the use of bis(trifluoromethanesulfonyl)imide (triflimide, (CF₃SO₂)₂NH, Tf₂NH). Being one of the strongest NH-acids, triflimide, and especially its salts, are widely used as catalysts in cycloaddition reactions, Friedel–Crafts reactions, condensation reactions, heterocyclization and many others. Triflamides act as a source of nitrogen in C-amination (sulfonamidation) reactions, the products of which are useful building blocks in organic synthesis, catalysts and ligands in metal complex catalysis, and have found applications in medicine. The addition reactions of triflamide in the presence of oxidizing agents to alkenes and dienes are considered separately. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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30 pages, 5674 KiB

Open AccessReview

Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine

by Biswajit Panda and Gianluigi Albano

Molecules 2021, 26(24), 7544; https://doi.org/10.3390/molecules26247544 - 13 Dec 2021

Cited by 8 | Viewed by 3952

Abstract

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity [...] Read more.

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity for humans, there is considerable interest in the development of synthetic analogues; in particular, conformationally restricted analogues of nicotine have emerged as promising drug molecules for selective nAChR-targeting ligands. In the present mini-review, we will describe the synthesis of the conformationally restricted analogues of nicotine involving one or more catalytic processes. In particular, we will follow a systematic approach as a function of the heteroarene structure, considering: (a) 2,3-annulated tricyclic derivatives; (b) 3,4-annulated tricyclic derivatives; (c) tetracyclic derivatives; and (d) other polycyclic derivatives. For each of them we will also consider, when carried out, biological studies on their activity for specific nAChR subunits. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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21 pages, 7608 KiB

Open AccessReview

Synthetic Strategies in the Preparation of Phenanthridinones

by Rajeshwar Reddy Aleti, Alexey A. Festa, Leonid G. Voskressensky and Erik V. Van der Eycken

Molecules 2021, 26(18), 5560; https://doi.org/10.3390/molecules26185560 - 13 Sep 2021

Cited by 15 | Viewed by 3712

Abstract

Phenanthridinones are important heterocyclic frameworks present in a variety of complex natural products, pharmaceuticals and displaying wide range of pharmacological actions. Its structural importance has evoked a great deal of interest in the domains of organic synthesis and medicinal chemistry to develop new [...] Read more.

Phenanthridinones are important heterocyclic frameworks present in a variety of complex natural products, pharmaceuticals and displaying wide range of pharmacological actions. Its structural importance has evoked a great deal of interest in the domains of organic synthesis and medicinal chemistry to develop new synthetic methodologies, as well as novel compounds of pharmaceutical interest. This review focuses on the synthesis of phenanthridinone scaffolds by employing aryl-aryl, N-aryl, and biaryl coupling reactions, decarboxylative amidations, and photocatalyzed reactions. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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75 pages, 18227 KiB

Open AccessReview

Thiazole Ring—A Biologically Active Scaffold

by Anthi Petrou, Maria Fesatidou and Athina Geronikaki

Molecules 2021, 26(11), 3166; https://doi.org/10.3390/molecules26113166 - 25 May 2021

Cited by 166 | Viewed by 10219

Abstract

Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is [...] Read more.

Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. Objective: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. Results: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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41 pages, 18554 KiB

Open AccessReview

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

by Annamaria Martorana, Gabriele La Monica and Antonino Lauria

Molecules 2020, 25(18), 4279; https://doi.org/10.3390/molecules25184279 - 18 Sep 2020

Cited by 43 | Viewed by 7062

Abstract

The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug [...] Read more.

The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized. Full article

(This article belongs to the Special Issue Biologically Active Heterocyclic Compounds)

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