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15 pages, 3098 KiB

Open AccessArticle

Quercetin-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer’s Agents

by Elisabete P. Carreiro, Ana R. Costa, Célia M. Antunes, Sofia Ernesto, Flávia Pinto, Beatriz Rodrigues and Anthony J. Burke

Molecules 2023, 28(22), 7495; https://doi.org/10.3390/molecules28227495 - 9 Nov 2023

Cited by 4 | Viewed by 2066

Abstract

The number of patients with Alzheimer’s disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. [...] Read more.

The number of patients with Alzheimer’s disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. Herein, we report the evaluation of a library of quercetin-1,2,3-triazole hybrids (I–IV) in antioxidant, hydrogen peroxide-induced oxidative stress protection, and cholinesterases (AChE and BuChE) inhibitory activities. Hybrids IIf and IVa-d showed potent in vitro inhibitory activity on eqBuChE (IC₅₀ values between 11.2 and 65.7 μM). Hybrid IIf, the best inhibitor, was stronger than galantamine, displaying an IC₅₀ value of 11.2 μM for eqBuChE, and is also a competitive inhibitor. Moreover, toxicity evaluation for the most promising hybrids was performed using the Artemia salina toxicity assay, showing low toxicity. Hybrids IIf, IVb, and IVd did not affect viability at 12.5 μM and also displayed a protective effect against oxidative stress induced by hydrogen peroxide in cell damage in MCF-7 cells. Hybrids IIf, IVb, and IVd act as multifunctional ligands in AD pathologies. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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20 pages, 3319 KiB

Open AccessArticle

Anti-Trypanosoma cruzi Activity, Mutagenicity, Hepatocytotoxicity and Nitroreductase Enzyme Evaluation of 3-Nitrotriazole, 2-Nitroimidazole and Triazole Derivatives

by Cheyene Almeida Celestino Menozzi, Rodolfo Rodrigo Florido França, Pedro Henrique Luccas, Mayara dos Santos Baptista, Tácio Vinício Amorim Fernandes, Lucas Villas Bôas Hoelz, Policarpo Ademar Sales Junior, Silvane Maria Fonseca Murta, Alvaro Romanha, Bárbara Verena Dias Galvão, Marcela de Oliveira Macedo, Alana da Cunha Goldstein, Carlos Fernando Araujo-Lima, Israel Felzenszwalb, Maria Cristina Nonato, Frederico Silva Castelo-Branco and Nubia Boechat

Molecules 2023, 28(22), 7461; https://doi.org/10.3390/molecules28227461 - 7 Nov 2023

Cited by 1 | Viewed by 2071

Abstract

Chagas disease (CD), which is caused by Trypanosoma cruzi and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the [...] Read more.

Chagas disease (CD), which is caused by Trypanosoma cruzi and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the search for new therapeutic options is urgent. In this study, nitroazole and azole compounds were synthesized and underwent molecular modeling, anti-T. cruzi evaluations and nitroreductase enzymatic assays. The compounds were designed as possible inhibitors of ergosterol biosynthesis and/or as substrates of nitroreductase enzymes. The in vitro evaluation against T. cruzi clearly showed that nitrotriazole compounds are significantly more potent than nitroimidazoles and triazoles. When their carbonyls were reduced to hydroxyl groups, the compounds showed a significant increase in activity. In addition, these substances showed potential for action via nitroreductase activation, as the substances were metabolized at higher rates than benznidazole (BZN), a reference drug against CD. Among the compounds, 1-(2,4-difluorophenyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)ethanol (8) is the most potent and selective of the series, with an IC₅₀ of 0.39 µM and selectivity index of 3077; compared to BZN, 8 is 4-fold more potent and 2-fold more selective. Moreover, this compound was not mutagenic at any of the concentrations evaluated, exhibited a favorable in silico ADMET profile and showed a low potential for hepatotoxicity, as evidenced by the high values of CC₅₀ in HepG2 cells. Furthermore, compared to BZN, derivative 8 showed a higher rate of conversion by nitroreductase and was metabolized three times more quickly when both compounds were tested at a concentration of 50 µM. The results obtained by the enzymatic evaluation and molecular docking studies suggest that, as planned, nitroazole derivatives may utilize the nitroreductase metabolism pathway as their main mechanism of action against Trypanosoma cruzi. In summary, we have successfully identified and characterized new nitrotriazole analogs, demonstrating their potential as promising candidates for the development of Chagas disease drug candidates that function via nitroreductase activation, are considerably selective and show no mutagenic potential. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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10 pages, 1470 KiB

Open AccessArticle

Design, Synthesis, and Antifungal Activity of Some Novel Phenylthiazole Derivatives Containing an Acylhydrazone Moiety

by Yao Tian, Jinchao Shi, Xiaoqian Deng, Tingyu Yu, Yong Hu, Richa Hu, Yufeng Lei, Linhua Yu, Xiang Zhu and Junkai Li

Molecules 2023, 28(20), 7084; https://doi.org/10.3390/molecules28207084 - 14 Oct 2023

Cited by 2 | Viewed by 1713

Abstract

Crop fungal diseases pose a serious threat to global crop production and quality. Developing new and efficient fungicides is an important measure to control crop diseases. Phenylthiazole was found to be an excellent antifungal skeleton based on our previous study on the structural [...] Read more.

Crop fungal diseases pose a serious threat to global crop production and quality. Developing new and efficient fungicides is an important measure to control crop diseases. Phenylthiazole was found to be an excellent antifungal skeleton based on our previous study on the structural optimization and biological activity of the natural product thiasporine A. To find new fungicides, 45 phenylthiazole derivatives containing an acylhydrazone moiety were designed and synthesized by the principle of active substructure splicing. Forty-two of the forty-five compounds are novel, except for compounds E1, E14, and E33. Their structures were structurally characterized by ¹H NMR, ¹³C NMR, and HRMS. The antifungal activities of the target compounds against Magnaporthe oryzae Colletotrichum camelliaet, Bipolaris maydis, and Sclerotinia sclerotiorum were evaluated at 25 μg/mL. The bioassay results revealed that most of these compounds exhibited excellent antifungal activities against M. oryzae and C. camelliaet at 25 μg/mL. In particular, compounds E4, E10, E14, E17, E23, E26, and E27 showed the inhibition rate of more than 80% against M. oryzae, with EC₅₀ values of 1.66, 2.01, 2.26, 1.45, 1.50, 1.29, and 2.65 μg/mL, respectively, which were superior to that of the commercial fungicides Isoprothiolane (EC₅₀ = 3.22 μg/mL) and Phenazine-1-carboxylic acid (EC₅₀ = 27.87 μg/mL). The preliminary structure–activity relationship (SAR) results suggested that introducing methyl, halogen, or methoxy at the ortho-position of R¹ and the para-position of R² can endow the final structure with excellent antifungal activity against M. oryzae. The current results provide useful data for developing phenylthiazole derivatives as new fungicides for controlling rice blast caused by M. oryzae. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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13 pages, 3715 KiB

Open AccessArticle

Naphthaleneoxypropargyl-Containing Piperazine as a Regulator of Effector Immune Cell Populations upon an Aseptic Inflammation

by Valentina K. Yu, Yelena S. Sycheva, Gulgul K. Kairanbayeva, Valery M. Dembitsky, Marina K. Balabekova, Aliya N. Tokusheva, Tulegen M. Seilkhanov, Tolganay Y. Zharkynbek, Anar Kh. Balapanova and Khaidar S. Tassibekov

Molecules 2023, 28(20), 7023; https://doi.org/10.3390/molecules28207023 - 11 Oct 2023

Cited by 1 | Viewed by 1386

Abstract

This study investigated the effects of aseptic inflammation and heavy metal exposure on immune responses, as well as the potential immunomodulatory properties of the newly synthesized 1-[1-(2,5-dimethoxyphenyl)-4-(naphthalene-1-yloxy)but-2-ynyl]-4-methylpiperazine complexed with β-cyclodextrin (β-CD). Aseptic inflammation was induced by a subcutaneous injection of turpentine in rats, [...] Read more.

This study investigated the effects of aseptic inflammation and heavy metal exposure on immune responses, as well as the potential immunomodulatory properties of the newly synthesized 1-[1-(2,5-dimethoxyphenyl)-4-(naphthalene-1-yloxy)but-2-ynyl]-4-methylpiperazine complexed with β-cyclodextrin (β-CD). Aseptic inflammation was induced by a subcutaneous injection of turpentine in rats, while heavy metal exposure was achieved through a daily administration of cadmium chloride and lead acetate. The levels of immune cell populations, including cytotoxic T lymphocytes (CTL), monocytes, and granulocytes, were assessed in the spleen. The results showed that aseptic inflammation led to decreased levels of CTL, monocytes, and granulocytes on the 14th day, indicating an inflammatory response accompanied by a migration of effector cells to the inflamed tissues. The exposure to cadmium chloride and lead acetate resulted in systemic immunotoxic effects, with reduced levels of B cells, CD4⁺ Th cells, monocytes, and granulocytes in the spleen. Notably, piperazine complexed with β-CD (the complex) exhibited significant stimulatory effects on CD4⁺, CD8⁺, and myeloid cell populations during aseptic inflammation, even in the presence of heavy metal exposure. These findings suggest the potential immunomodulatory properties of the complex in the context of aseptic inflammation and heavy metal exposure. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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22 pages, 3707 KiB

Open AccessArticle

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3′-oxindoles] under Microwave Irradiation and Their Anticancer Activity

by Richa Sharma, Lalit Yadav, Ali Adnan Nasim, Ravi Kant Yadav, Rui Hong Chen, Neha Kumari, Fan Ruiqi, Ashoke Sharon, Nawal Kishore Sahu, Sirish Kumar Ippagunta, Paolo Coghi, Vincent Kam Wai Wong and Sandeep Chaudhary

Molecules 2023, 28(18), 6503; https://doi.org/10.3390/molecules28186503 - 7 Sep 2023

Cited by 2 | Viewed by 1789

Abstract

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a–b, a number of α-amino acids 2a–e and (E)-2-aryl-1-nitroethenes 3a–e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation [...] Read more.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a–b, a number of α-amino acids 2a–e and (E)-2-aryl-1-nitroethenes 3a–e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using ¹H and ¹³C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3′-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3′-oxindoles] analogs 4a–w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3′-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC₅₀ = 34.99–47.92 µM; SI = 0.96–2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC₅₀ = 41.56–86.53 µM; SI = 0.49–0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC₅₀ = 100 µM) and chloroquine (IC₅₀ = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC₅₀ = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC₅₀ = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line]. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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16 pages, 3505 KiB

Open AccessArticle

New Heterocyclic Compounds from Oxazol-5(4H)-one and 1,2,4-Triazin-6(5H)-one Classes: Synthesis, Characterization and Toxicity Evaluation

by Stefania-Felicia Barbuceanu, Elena-Valentina Rosca, Theodora-Venera Apostol, Laura-Ileana Socea, Constantin Draghici, Ileana Cornelia Farcasanu, Lavinia Liliana Ruta, George Mihai Nitulescu, Lucian Iscrulescu, Elena-Mihaela Pahontu, Rica Boscencu, Gabriel Saramet and Octavian Tudorel Olaru

Molecules 2023, 28(12), 4834; https://doi.org/10.3390/molecules28124834 - 17 Jun 2023

Cited by 4 | Viewed by 2230

Abstract

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium [...] Read more.

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, ¹H-NMR, ¹³C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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21 pages, 1418 KiB

Open AccessFeature PaperArticle

Synthesis and Biological Evaluation of New Schiff Bases Derived from 4-Amino-5-(3-fluorophenyl)-1,2,4-triazole-3-thione

by Sara Janowska, Dmytro Khylyuk, Michał Janowski, Urszula Kosikowska, Paulina Strzyga-Łach, Marta Struga and Monika Wujec

Molecules 2023, 28(6), 2718; https://doi.org/10.3390/molecules28062718 - 17 Mar 2023

Cited by 8 | Viewed by 3021

Abstract

The treatment of infectious diseases is a challenging issue faced by the medical community. The emergence of drug-resistant strains of bacteria and fungi is a major concern. Researchers and medical professionals are working to develop new and innovative treatments for infectious diseases. Schiff [...] Read more.

The treatment of infectious diseases is a challenging issue faced by the medical community. The emergence of drug-resistant strains of bacteria and fungi is a major concern. Researchers and medical professionals are working to develop new and innovative treatments for infectious diseases. Schiff bases are one a promising class of compounds. In this work, new derivatives were obtained of the 4-amino-5-(3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione reaction, with corresponding benzaldehydes with various substituents at position 4. The antibacterial and antifungal activities of all synthesized compounds were tested. Several new substances have shown moderate antifungal activity against Candida spp. The highest activity directed against C. albicans was shown by compound RO4, with a 4-methoxyphenyl moiety and an MIC value of 62.5 µg/mL. In order to check the toxicity of the synthesized compounds, their effect on cell lines was examined. Additionally, we tried to elucidate the mechanism of the antibacterial and antifungal activity of the tested compounds using molecular docking to topoisomerase IV, D-Alanyl-D-Alanine Ligase, and dihydrofolate reductase. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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24 pages, 6939 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer

by Yu-Chan Wang, Rong-Hong Zhang, Sheng-Cao Hu, Hong Zhang, Dan Yang, Wen-Li Zhang, Yong-Long Zhao, Dong-Bing Cui, Yong-Jun Li, Wei-Dong Pan, Shang-Gao Liao and Meng Zhou

Molecules 2022, 27(13), 4040; https://doi.org/10.3390/molecules27134040 - 23 Jun 2022

Cited by 3 | Viewed by 2708

Abstract

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. [...] Read more.

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC₅₀ value of 0.57 μM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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20 pages, 3879 KiB

Open AccessArticle

Facile Synthesis of Functionalized Phenoxy Quinolines: Antibacterial Activities against ESBL Producing Escherichia coli and MRSA, Docking Studies, and Structural Features Determination through Computational Approach

by Mahwish Arshad, Nasir Rasool, Muhammad Usman Qamar, Syed Adnan Ali Shah and Zainul Amiruddin Zakaria

Molecules 2022, 27(12), 3732; https://doi.org/10.3390/molecules27123732 - 10 Jun 2022

Cited by 6 | Viewed by 2145

Abstract

The synthesis of new 6-Bromoquinolin-4-ol derivatives (3a–3h) by Chan–Lam coupling utilizing different types of solvents (protic, aprotic, and mixed solvents) and bases was studied in the present manuscript. Furthermore, their potential against ESBL producing Escherichia coli (ESBL E. coli [...] Read more.

The synthesis of new 6-Bromoquinolin-4-ol derivatives (3a–3h) by Chan–Lam coupling utilizing different types of solvents (protic, aprotic, and mixed solvents) and bases was studied in the present manuscript. Furthermore, their potential against ESBL producing Escherichia coli (ESBL E. coli) and methicillin-resistant Staphylococcusaureus (MRSA) were investigated. Commercially available 6-bromoquinolin-4-ol (3a) was reacted with different types of aryl boronic acids along with Cu(OAc)₂ via Chan–Lam coupling methodology utilizing the protic and aprotic and mixed solvents. The molecules (3a–3h) exhibited very good yields with methanol, moderate yields with DMF, and low yields with ethanol solvents, while the mixed solvent CH₃OH/H₂O (8:1) gave more excellent results as compared to the other solvents. The in vitro antiseptic values against ESBL E. coli and MRSA were calculated at five different deliberations (10, 20, 30, 40, 50 mg/well) by agar well diffusion method. The molecule 3e depicted highest antibacterial activity while compounds 3b and 3d showed low antibacterial activity. Additionally, MIC and MBC standards were calculated against the established bacteria by broth dilution method. Furthermore, a molecular docking investigation of the derivatives (3a–3h) were performed. Compound (3e) was highly active and depicted the least binding energy of −5.4. Moreover, to investigate the essential structural and physical properties, the density functional theory (DFT) findings of the synthesized molecules were accomplished by using the basic set PBE0-D3BJ/def2-TZVP/SMD water level of the theory. The synthesized compounds showed an energy gap from 4.93 to 5.07 eV. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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Review

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19 pages, 4629 KiB

Open AccessReview

Molecular Hybridization of Alkaloids Using 1,2,3-Triazole-Based Click Chemistry

by Devan Buchanan, Ashley M. Pham, Sandeep K. Singh and Siva S. Panda

Molecules 2023, 28(22), 7593; https://doi.org/10.3390/molecules28227593 - 14 Nov 2023

Cited by 7 | Viewed by 1999

Abstract

Alkaloids found in multiple species, known as ‘driver species’, are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click [...] Read more.

Alkaloids found in multiple species, known as ‘driver species’, are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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52 pages, 20271 KiB

Open AccessReview

Flavones and Related Compounds: Synthesis and Biological Activity

by Denisa Leonte, Daniel Ungureanu and Valentin Zaharia

Molecules 2023, 28(18), 6528; https://doi.org/10.3390/molecules28186528 - 8 Sep 2023

Cited by 9 | Viewed by 5559

Abstract

This review focuses on the synthesis and biological activity of flavones and their related flavonoidic compounds, namely flavonols and aurones. Among the biological activities of natural and synthetic flavones and aurones, their anticancer, antioxidant, and antimicrobial properties are highlighted and detailed in this [...] Read more.

This review focuses on the synthesis and biological activity of flavones and their related flavonoidic compounds, namely flavonols and aurones. Among the biological activities of natural and synthetic flavones and aurones, their anticancer, antioxidant, and antimicrobial properties are highlighted and detailed in this review. Starting from the structures of natural flavones acting on multiple anticancer targets (myricetin, genkwanin, and other structurally related compounds), new flavone analogs were recently designed and evaluated for their anticancer activity. The most representative compounds and their anticancer activity are summarized in this review. Natural flavones recognized for their antimicrobial properties (baicalein, luteolin, quercetol, apigenin, kaempferol, tricin) have been recently derivatized or structurally modulated by chemical synthetic methods in order to obtain new effective antimicrobial flavonoidic derivatives with improved biological properties. The most promising antimicrobial agents are systematically highlighted in this review. The most applied method for the synthesis of flavones and aurones is based on the oxidative cyclization of o-hydroxychalcones. Depending on the reaction conditions and the structure of the precursor, in some cases, several cyclization products result simultaneously: flavones, flavanones, flavonols, and aurones. Based on the literature data and the results obtained by our research group, our aim is to highlight the most promising methods for the synthesis of flavones, as well as the synthetic routes for the other structurally related cyclization products, such as hydroxyflavones and aurones, while considering that, in practice, it is difficult to predict which is the main or exclusive cyclization product of o-hydroxychalcones under certain reaction conditions. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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32 pages, 2780 KiB

Open AccessReview

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

by George Mihai Nitulescu, Gheorghe Stancov, Oana Cristina Seremet, Georgiana Nitulescu, Dragos Paul Mihai, Cosmina Gabriela Duta-Bratu, Stefania Felicia Barbuceanu and Octavian Tudorel Olaru

Molecules 2023, 28(14), 5359; https://doi.org/10.3390/molecules28145359 - 12 Jul 2023

Cited by 19 | Viewed by 4102

Abstract

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed [...] Read more.

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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23 pages, 4538 KiB

Open AccessReview

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

by Andrea Angeli, Niccolò Paoletti and Claudiu T. Supuran

Molecules 2023, 28(7), 3220; https://doi.org/10.3390/molecules28073220 - 4 Apr 2023

Cited by 11 | Viewed by 3684

Abstract

The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite [...] Read more.

The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite the importance of oxygen and nitrogen five-membered heterocyclic aromatic rings in medicinal chemistry, the installation of sulfonamide moiety on such heterocycles has not received much attention. On the other hand, 1,3,4-thiadiazole/thiadiazoline ring-bearing sulfonamides are the scaffolds which have been widely used in a variety of pharmaceutically important CAIs such as acetazolamide, metazolamide and their many derivatives obtained by using the tail approach. Here, we reviewed the field focusing on the diverse biological activities of these CAIs, such as antiglaucoma, antiepileptic, antitumor and antiinfective properties. This review highlights developments involving five-membered heterocyclic sulfonamides over the last years, with a focus on their pharmacological/clinical applications. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)

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