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23 pages, 5178 KiB

Open AccessArticle

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

by Patrícia S. M. Amado, Inês C. C. Costa, José A. Paixão, Ricardo F. Mendes, Sofia Cortes and Maria L. S. Cristiano

Molecules 2022, 27(17), 5401; https://doi.org/10.3390/molecules27175401 - 24 Aug 2022

Cited by 7 | Viewed by 2183

Abstract

Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1 [...] Read more.

Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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12 pages, 1770 KiB

Open AccessArticle

Aza-Oxa-Triazole Based Macrocycles with Tunable Properties: Design, Synthesis, and Bioactivity

by Subba Rao Cheekatla, Liya Thurakkal, Anna Jose, Debashis Barik and Mintu Porel

Molecules 2022, 27(11), 3409; https://doi.org/10.3390/molecules27113409 - 25 May 2022

Cited by 7 | Viewed by 3036

Abstract

A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been rendered to achieve the tunable property. These aza-oxa-based macrocycles can also differ in the number of heteroatoms in the backbone [...] Read more.

A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been rendered to achieve the tunable property. These aza-oxa-based macrocycles can also differ in the number of heteroatoms in the backbone and the ring size of the macrocycles. For the proof of concept, a library of macrocycles was synthesized with various hanging functional groups, different combinations of heteroatoms, and ring sizes in the range of 17–27 atoms and was characterized by NMR and mass spectrometry. In light of the importance of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and the significance of triazole groups for various applications, we employed the click-reaction-based macrocyclization. The competence of the synthesized macrocycles in various biomedical applications was proven by studying the interactions with the serum albumin proteins; bovine serum albumin and human serum albumin. It was observed that some candidates, based on their hanging functional groups and specific backbone atoms, could interact well with the protein, thus improving the bioactive properties. On the whole, this work is a proof-of-concept to explore the backbone- and side-chain-tunable macrocycle for different properties and applications. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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16 pages, 10056 KiB

Open AccessArticle

Synthesis and Structure–Activity Relationship of Thioacetamide-Triazoles against Escherichia coli

by Suresh Dharuman, Miranda J. Wallace, Stephanie M. Reeve, Jürgen B. Bulitta and Richard E. Lee

Molecules 2022, 27(5), 1518; https://doi.org/10.3390/molecules27051518 - 24 Feb 2022

Cited by 7 | Viewed by 2696

Abstract

Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted [...] Read more.

Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-E. coli structure–activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure–activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced; the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and N-benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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18 pages, 2787 KiB

Open AccessArticle

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives

by Bartosz Skóra, Anna Lewińska, Anna Kryshchyshyn-Dylevych, Danylo Kaminskyy, Roman Lesyk and Konrad A. Szychowski

Molecules 2022, 27(3), 894; https://doi.org/10.3390/molecules27030894 - 28 Jan 2022

Cited by 21 | Viewed by 3498

Abstract

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be [...] Read more.

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be a basis for the search for new potential drugs. Therefore, the aim of this study was to evaluate the cytotoxic, cytostatic, and antibacterial effects of certain 4-thiazolidinone-based derivatives, Les-3166, Les-5935, Les-6009, and Les-6166, on human fibroblasts (BJ), neuroblastoma (SH-SY5Y), epithelial lung carcinoma (A549), and colorectal adenocarcinoma (CACO-2) cell lines in vitro. All tested compounds applied in a concentration range from 10 to 100 µM were able to decrease metabolic activity in the BJ, A549, and SH-SY5Y cell lines. However, the action of Les-3166 was mainly based on the ROS-independent pathway, similarly to Les-6009. In turn, Les-5935 and Les-6166 were able to promote ROS production in BJ, A549, and SH-SY5Y cells, compared to the control. Les-3166, Les-6009, and Les-6166 significantly increased the caspase-3 activity, especially at the concentrations of 50 µM and 100 µM. However, Les-5935 did not induce apoptosis. Only Les-5935 showed a minor cytostatic effect on SH-SY5Y cells. Additionally, the antibacterial properties of the tested compounds against P. aeruginosa bacterial biofilm can be ranked as follows: Les-3166 > Les-5935 > Les-6009. Les-6166 did not show any anti-biofilm activity. In summary, the study showed that Les-5935, Les-6009, and Les-6166 were characterized by anticancer properties, especially in the human lung cancer cell. In cases of BJ, SH-SY5Y, and CACO-2 cells the anticancer usage of such compounds is limited due to effect visible only at 50 and 100 µM. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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21 pages, 1479 KiB

Open AccessArticle

Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens

by Dovilė Malūkaitė, Birutė Grybaitė, Rita Vaickelionienė, Giedrius Vaickelionis, Birutė Sapijanskaitė-Banevič, Povilas Kavaliauskas and Vytautas Mickevičius

Molecules 2022, 27(1), 74; https://doi.org/10.3390/molecules27010074 - 23 Dec 2021

Cited by 14 | Viewed by 4114

Abstract

Rapidly growing antimicrobial resistance among clinically important bacterial and fungal pathogens accounts for high morbidity and mortality worldwide. Therefore, it is critical to look for new small molecules targeting multidrug-resistant pathogens. Herein, in this paper we report a synthesis, ADME properties, and in [...] Read more.

Rapidly growing antimicrobial resistance among clinically important bacterial and fungal pathogens accounts for high morbidity and mortality worldwide. Therefore, it is critical to look for new small molecules targeting multidrug-resistant pathogens. Herein, in this paper we report a synthesis, ADME properties, and in vitro antimicrobial activity characterization of novel thiazole derivatives bearing β-amino acid, azole, and aromatic moieties. The in silico ADME characterization revealed that compounds 1–9 meet at least 2 Lipinski drug-like properties while cytotoxicity studies demonstrated low cytotoxicity to Vero cells. Further in vitro antimicrobial activity characterization showed the selective and potent bactericidal activity of 2a–c against Gram-positive pathogens (MIC 1–64 µg/mL) with profound activity against S. aureus (MIC 1–2 µg/mL) harboring genetically defined resistance mechanisms. Furthermore, the compounds 2a–c exhibited antifungal activity against azole resistant A. fumigatus, while only 2b and 5a showed antifungal activity against multidrug resistant yeasts including Candida auris. Collectively, these results demonstrate that thiazole derivatives 2a–c and 5a could be further explored as a promising scaffold for future development of antifungal and antibacterial agents targeting highly resistant pathogenic microorganisms. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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21 pages, 4621 KiB

Open AccessArticle

Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane

by Leo Štefan, Ana Čikoš, Robert Vianello, Ivica Đilović, Dubravka Matković-Čalogović and Miljenko Dumić

Molecules 2021, 26(22), 7032; https://doi.org/10.3390/molecules26227032 - 21 Nov 2021

Cited by 1 | Viewed by 2419

Abstract

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under [...] Read more.

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 2₁/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF₄. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6_, monoclinic, space group P 2₁/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 2₁/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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20 pages, 51802 KiB

Open AccessArticle

Synthesis and Toxicity Evaluation of New Pyrroles Obtained by the Reaction of Activated Alkynes with 1-Methyl-3-(cyanomethyl)benzimidazolium Bromide

by Beatrice-Cristina Ivan, Florea Dumitrascu, Adriana Iuliana Anghel, Robert Viorel Ancuceanu, Sergiu Shova, Denisa Dumitrescu, Constantin Draghici, Octavian Tudorel Olaru, George Mihai Nitulescu, Mihaela Dinu and Stefania-Felicia Barbuceanu

Molecules 2021, 26(21), 6435; https://doi.org/10.3390/molecules26216435 - 25 Oct 2021

Cited by 4 | Viewed by 2659

Abstract

A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new tri- and tetra-substituted N-arylpyrroles were synthesized by the one-pot reaction of 1-methyl-3-cyanomethyl benzimidazolium bromide with substituted [...] Read more.

A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new tri- and tetra-substituted N-arylpyrroles were synthesized by the one-pot reaction of 1-methyl-3-cyanomethyl benzimidazolium bromide with substituted alkynes having at least one electron-withdrawing substituent, in 1,2-epoxybutane, acting both as the solvent and reagent to generate the corresponding benzimidazolium N3-ylide. The structural characterization of the new substituted pyrroles was based on IR, NMR spectroscopy as well as on single crystal X-ray analysis. The toxicity of the new compounds was assessed on the plant cell using Triticum aestivum L. species and on the animal cell using Artemia franciscana Kellogg and Daphnia magna Straus crustaceans. The compounds showed minimal phytotoxicity on Triticum rootlets and virtually no acute toxicity on Artemia nauplii, while on Daphnia magna, it induced moderate to high toxicity, similar to nifedipine. Our research indicates that the newly synthetized pyrrole derivatives are promising molecules with biological activity and low acute toxicity. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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10 pages, 2287 KiB

Open AccessArticle

Synthesis of Halogenated 1,5-Diarylimidazoles and Their Inhibitory Effects on LPS-Induced PGE₂ Production in RAW 264.7 Cells

by Zunhua Yang, Yuanying Fang, Jae-Min Kim, Kyung-Tae Lee and Haeil Park

Molecules 2021, 26(20), 6093; https://doi.org/10.3390/molecules26206093 - 9 Oct 2021

Cited by 1 | Viewed by 1833

Abstract

A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE₂ production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated [...] Read more.

A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE₂ production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles, regardless of the species of halogen, exhibited very strong inhibitory activities of PGE₂ production. Among them, 4-chloro-5-(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole (3, IC₅₀ 3.3 nM ± 2.93), and 4-chloro-5-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)imidazole (13, IC₅₀ 5.3 nM ± 0.23) showed the best results. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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24 pages, 7025 KiB

Open AccessArticle

Oxazinethione Derivatives as a Precursor to Pyrazolone and Pyrimidine Derivatives: Synthesis, Biological Activities, Molecular Modeling, ADME, and Molecular Dynamics Studies

by Magda H. Abdellattif, Mohd Shahbaaz, M. M. H. Arief and Mostafa A. Hussien

Molecules 2021, 26(18), 5482; https://doi.org/10.3390/molecules26185482 - 9 Sep 2021

Cited by 9 | Viewed by 2361

Abstract

In this study, we used oxazinethione as a perfect precursor to synthesize new pyrimidine and pyrazole derivatives with potent biological activities. Biological activities were determined for all compounds against A. flavus, E. coli, S. aureus, and F. moniliform. Compounds 3, 4a-b [...] Read more.

In this study, we used oxazinethione as a perfect precursor to synthesize new pyrimidine and pyrazole derivatives with potent biological activities. Biological activities were determined for all compounds against A. flavus, E. coli, S. aureus, and F. moniliform. Compounds 3, 4a-b, and 5 exhibited higher activities toward A. flavus, E. coli, S. aureus, and F. moniliform; this was indicated through the MIC (minimum inhibitory concentration). At the same time, anticancer activities were determined through four cell lines, Ovcar-3, Hela, MCF-7, and LCC-MMk. The results obtained indicated that compound 5 was the most potent compound for both cell lines. Molecular docking was studied by the MOE (molecular operating environment). The in silico ADME of compounds 2 and 5 showed good pharmacokinetic properties. The present research strengthens the applicability of these compounds as encouraging anticancer and antibacterial drugs. Moreover, JAGUAR module MD simulations were carried out at about 100 ns. In addition, spectroscopic studies were carried out to establish the reactions of the synthesized structure derivatives. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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6 pages, 1202 KiB

Open AccessCommunication

A Novel Approach to the Synthesis of 1,3,4-Thiadiazole-2-amine Derivatives

by Tatiana S. Kokovina, Svyatoslav Y. Gadomsky, Alexei A. Terentiev and Nataliya A. Sanina

Molecules 2021, 26(17), 5159; https://doi.org/10.3390/molecules26175159 - 25 Aug 2021

Cited by 10 | Viewed by 5023

Abstract

The main purpose of the study was the development of a new method for synthesis of 1,3,4-thiadiazol-2-amine derivatives in a one-pot manner using the reaction between a thiosemicarbazide and carboxylic acid without toxic additives such as POCl₃ or SOCl₂. The [...] Read more.

The main purpose of the study was the development of a new method for synthesis of 1,3,4-thiadiazol-2-amine derivatives in a one-pot manner using the reaction between a thiosemicarbazide and carboxylic acid without toxic additives such as POCl₃ or SOCl₂. The reaction was investigated in the presence of polyphosphate ester (PPE). It was found that, in the presence of PPE, the reaction between the thiosemicarbazide and carboxylic acid proceeds in one-pot through three steps with the formation of corresponding 2-amino-1,3,4-thiadiazole. Using the developed approach five, 2-amino-1,3,4-thiadiazoles were synthesized. The structures of all compounds were proven by mass spectrometry, IR, and NMR spectroscopies. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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23 pages, 2887 KiB

Open AccessArticle

Synthesis, In Silico and In Vitro Evaluation of Antimicrobial and Toxicity Features of New 4-[(4-Chlorophenyl)sulfonyl]benzoic Acid Derivatives

by Theodora-Venera Apostol, Mariana Carmen Chifiriuc, Constantin Draghici, Laura-Ileana Socea, Luminita Gabriela Marutescu, Octavian Tudorel Olaru, George Mihai Nitulescu, Elena Mihaela Pahontu, Gabriel Saramet and Stefania-Felicia Barbuceanu

Molecules 2021, 26(16), 5107; https://doi.org/10.3390/molecules26165107 - 23 Aug 2021

Cited by 5 | Viewed by 3109

Abstract

The multi-step synthesis, physico-chemical characterization, and biological activity of novel valine-derived compounds, i.e., N-acyl-α-amino acids, 1,3-oxazol-5(4H)-ones, N-acyl-α-amino ketones, and 1,3-oxazoles derivatives, bearing a 4-[(4-chlorophenyl)sulfonyl]phenyl moiety are reported here. The structures of the newly synthesized compounds were confirmed by spectral [...] Read more.

The multi-step synthesis, physico-chemical characterization, and biological activity of novel valine-derived compounds, i.e., N-acyl-α-amino acids, 1,3-oxazol-5(4H)-ones, N-acyl-α-amino ketones, and 1,3-oxazoles derivatives, bearing a 4-[(4-chlorophenyl)sulfonyl]phenyl moiety are reported here. The structures of the newly synthesized compounds were confirmed by spectral (UV-Vis, FT-IR, MS, ¹H- and ¹³C-NMR) data and elemental analysis results, and their purity was determined by RP-HPLC. The new compounds were assessed for their antimicrobial activity and toxicity to aquatic crustacean Daphnia magna. Also, in silico studies regarding their potential mechanism of action and toxicity were performed. The antimicrobial evaluation revealed that the 2-{4-[(4-chlorophenyl)sulfonyl]benzamido}-3-methylbutanoic acid and the corresponding 1,3-oxazol-5(4H)-one exhibited antimicrobial activity against Gram-positive bacterial strains and the new 1,3-oxazole containing a phenyl group at 5-position against the C. albicans strain. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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21 pages, 11500 KiB

Open AccessArticle

Synthesis of 3,5-Bis(trifluoromethyl)phenyl-Substituted Pyrazole Derivatives as Potent Growth Inhibitors of Drug-Resistant Bacteria

by Ibrahim S. Alkhaibari, Hansa Raj KC, Subrata Roy, Mohd. K. Abu-gazleh, David F. Gilmore and Mohammad A. Alam

Molecules 2021, 26(16), 5083; https://doi.org/10.3390/molecules26165083 - 22 Aug 2021

Cited by 6 | Viewed by 2870

Abstract

Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are [...] Read more.

Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds 11, 28, and 29 are potent against S. aureus biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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13 pages, 1097 KiB

Open AccessArticle

Structure and IR Spectra of 3(5)-Aminopyrazoles and UV-Induced Tautomerization in Argon Matrix

by Alina Secrieru, Susy Lopes, Maria L. S. Cristiano and Rui Fausto

Molecules 2021, 26(14), 4299; https://doi.org/10.3390/molecules26144299 - 15 Jul 2021

Cited by 5 | Viewed by 2221

Abstract

The prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ [...] Read more.

The prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol⁻¹; Gibbs free energy difference: 9.8 kJ mol⁻¹). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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22 pages, 15310 KiB

Open AccessArticle

Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates

by Gita Matulevičiūtė, Eglė Arbačiauskienė, Neringa Kleizienė, Vilija Kederienė, Greta Ragaitė, Miglė Dagilienė, Aurimas Bieliauskas, Vaida Milišiūnaitė, Frank A. Sløk and Algirdas Šačkus

Molecules 2021, 26(13), 3808; https://doi.org/10.3390/molecules26133808 - 22 Jun 2021

Cited by 5 | Viewed by 3331

Abstract

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and ( [...] Read more.

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by ¹H-, ¹³C-, and ¹⁵N-NMR spectroscopy and HRMS investigation. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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13 pages, 1479 KiB

Open AccessArticle

CuI-Catalyzed Coupling Reactions of 4-Iodopyrazoles and Alcohols: Application toward Withasomnine and Homologs

by Yoshihide Usami, Yumika Kubo, Toshiki Takagaki, Nao Kuroiwa, Jun Ono, Kohei Nishikawa, Ayaka Nakamizu, Yuya Tatsui, Shinya Harusawa, Noboru Hayama and Hiroki Yoneyama

Molecules 2021, 26(11), 3370; https://doi.org/10.3390/molecules26113370 - 2 Jun 2021

Cited by 2 | Viewed by 2686

Abstract

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C [...] Read more.

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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12 pages, 2785 KiB

Open AccessArticle

Experimental and Theoretical Mechanistic Study on the Thermal Decomposition of 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline

by Karolina Kula, Agnieszka Kącka-Zych, Agnieszka Łapczuk-Krygier, Zbigniew Wzorek, Anna K. Nowak and Radomir Jasiński

Molecules 2021, 26(5), 1364; https://doi.org/10.3390/molecules26051364 - 4 Mar 2021

Cited by 21 | Viewed by 2213

Abstract

The present paper is a continuation of comprehensive study regarding to synthesis and properties of pyrazoles and their derivatives. In its framework an experimental and theoretical studies of thermal decomposition of the 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline were performed. It was found, that the decompositions of the [...] Read more.

The present paper is a continuation of comprehensive study regarding to synthesis and properties of pyrazoles and their derivatives. In its framework an experimental and theoretical studies of thermal decomposition of the 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline were performed. It was found, that the decompositions of the mentioned pyrazoline system in the solution and at the melted state proceed via completely different molecular mechanisms. These mechanisms have been explained in the framework of the Molecular Electron Density Theory (MEDT) with the computational level of B3LYP/6-31G(d). A Bonding Evolution Theory (BET) examination of dehydrochlorination of the 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline permits elucidation of the molecular mechanism. It was found, that on the contrary for most known HCl extrusion processes in solution, this reaction is realised via single-step mechanism. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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64 pages, 54856 KiB

Open AccessReview

Substituted Pyrazoles and Their Heteroannulated Analogs—Recent Syntheses and Biological Activities

by Mohamed Ramadan, Ashraf A. Aly, Lamiaa E. Abd El-Haleem, Mohammed B. Alshammari and Stefan Bräse

Molecules 2021, 26(16), 4995; https://doi.org/10.3390/molecules26164995 - 18 Aug 2021

Cited by 18 | Viewed by 4917

Abstract

Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until [...] Read more.

Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until 2020, for the synthesis of pyrazoles, their heteroannulated derivatives, and their applications as biologically active moieties. Moreover, we focused on traditional procedures used in the synthesis of pyrazoles. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Biological Studies of Five-Membered Azaheterocycle Derivatives)

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