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Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

ABSTRACT: The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydrazine carbothioamide (Rx-6) and pyridine 2-yl-methylene hydrazine carboxamide (Rx-7) IC50 = 1.07 ± 0.043 µM, 2.18 ± 0.058 µM both possessed significant activity. Furthermore, molecular docking and kinetic studies were performed for the most potent inhibitors to demonstrate the binding mode of the active pyridine carbothioamide with the enzyme urease and its mode of interaction. The ADME profile also showed that all the synthesized molecules present oral bioavailability and high GI absorption.

SUBMITTER: Naseer A

PROVIDER: S-EPMC9609714 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

Naseer Ayesha A Osra Faisal Abdulrhman FA Awan Asia Naz AN Imran Aqeel A Hameed Abdul A Ali Shah Syed Adnan SA Iqbal Jamshed J Zakaria Zainul Amiruddin ZA

Pharmaceuticals (Basel, Switzerland) 20221019 10

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydraz ...[more]

PMID: 36297400

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Project description:BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) have been the most commonly used class of medications worldwide for the last three decades.ObjectivesThis study aimed to design and synthesize a novel series of methoxyphenyl thiazole carboxamide derivatives and evaluate their cyclooxygenase (COX) suppressant and cytotoxic properties.MethodsThe synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and were evaluated for their selectivity towards COX-1 and COX-2 using an in vitro COX inhibition assay kit. Besides, their cytotoxicity was evaluated using the Sulforhodamine B (SRB) assay. Moreover, molecular docking studies were conducted to identify the possible binding patterns of these compounds within both COX-1 and COX-2 isozymes, utilizing human X-ray crystal structures. The density functional theory (DFT) analysis was used to evaluate compound chemical reactivity, which was determined by calculating the frontier orbital energy of both HOMO and LUMO orbitals, as well as the HOMO-LUMO energy gap. Finally, the QiKProp module was used for ADME-T analysis.ResultsThe results revealed that all synthesized molecules have potent inhibitory activities against COX enzymes. The percentage of inhibitory activities at 5 µM concentration against the COX2 enzyme was in the range of 53.9-81.5%, while the percentage against the COX-1 enzyme was 14.7-74.8%. That means almost all of our compounds have selective inhibition activities against the COX-2 enzyme, and the most selective compound was 2f, with selectivity ratio (SR) value of 3.67 at 5 µM concentration, which has a bulky group of trimethoxy on the phenyl ring that could not bind well with the COX-1 enzyme. Compound 2h was the most potent, with an inhibitory activity percentage at 5 µM concentration of 81.5 and 58.2% against COX-2 and COX-1, respectively. The cytotoxicity of these compounds was evaluated against three cancer cell lines: Huh7, MCF-7, and HCT116, and negligible or very weak activities were observed for all of these compounds except compound 2f, which showed moderate activities with IC50 values of 17.47 and 14.57 µM against Huh7 and HCT116 cancer cell lines, respectively. Analysis of the molecular docking suggests 2d, 2e, 2f, and 2i molecules were bound to COX-2 isozyme favorably over COX-1 enzyme, and their interaction behaviors within COX-1 and COX-2 isozymes were comparable to celecoxib, as an ideal selective COX-2 drug, which explained their high potency and COX-2 selectivity. The molecular docking scores and expected affinity using the MM-GBSA approach were consistent with the recorded biological activity. The calculated global reactivity descriptors, such as HOMO and LUMO energies and the HOMO-LUMO gaps, confirmed the key structural features required to achieve favorable binding interactions and thus improve affinity. The in silico ADME-T studies asserted the druggability of molecules and have the potential to become lead molecules in the drug discovery process.ConclusionIn general, the series of the synthesized compounds had a strong effect on both enzymes (COX-1 and COX-2) and the trimethoxy compound 2f was more selective than the other compounds.

Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are considered one of the most commonly used medications globally. Seventeen isoxazole-containing compounds with various functional groups were evaluated in this work to identify which one was the most potent and which group was most selective toward COX-1 and COX-2 by using an in vitro COX inhibition assay kit. Their cytotoxicity was evaluated on the normal hepatic cell line (LX-2) utilizing the MTS assay. Moreover, these molecules' antibacterial and antifungal activities were evaluated using a microdilution assay against several bacterial and fungal species. In addition, molecular docking studies were conducted to identify the possible binding interactions between these compounds and their biological targets by using the X-ray crystal structure of the human COX enzyme and different proteins of bacterial and fungal strains. At the same time, the QiKProp module was used for ADME-T analysis. The results showed that all evaluated isoxazole derivatives showed moderate to potent activities against COX enzymes. The most potent compound against COX-1 and COX-2 enzymes was A13, with IC50 values of 64 and 13 nM, respectively, and a significant selectivity ratio of 4.63. It was clear that the 3,4-dimethoxy substitution on the first phenyl ring and the Cl atom on the other phenyl pushed the 5-methyl-isoxazole ring toward the secondary binding pocket and created the ideal binding interactions with the COX-2 enzyme in comparison with the other compounds. Compound A8 showed antibacterial and antifungal activities against Pseudomonas aeruginosa, Klebsiella pneumonia, and Candida albicans with MIC values of 2 mg/ml. In fact, this compound showed possible binding interactions with the elastase in P. aeruginosa and KPC-2 carbapenemase in K. pneumonia. Furthermore, for better understanding, molecular dynamics simulations were undertaken to study the change in dynamicity of the protein backbone and ligand after the ligand binds to the protein and to ensure the stability of ligand-protein complexes.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-022-03408-8.

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Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

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Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

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