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Design, Synthesis, and Biological Effect Studies of Novel Benzofuran-Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors.

ABSTRACT: In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new compounds containing thiazolylhydrazone groups were synthesized. The structures of the obtained compounds were elucidated by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS) methods. The inhibitory effects of the final compounds on MAO enzymes were investigated by means of in vitro methods. In addition to enzyme inhibition studies, enzyme kinetic studies of compounds with high inhibitory activity were examined, and their effects on substrate-enzyme relations were investigated. Additionaly, cytotoxicity tests were carried out to determine the toxicities of the selected compounds, and the compounds were found to be nontoxic. The interactions of the active compound with the active site of the enzyme were characterized by in silico methods.

SUBMITTER: Osmani Ye D

PROVIDER: S-EPMC10938434 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Effect Studies of Novel Benzofuran-Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors.

Osmani Ye Derya D Sağlik Begüm Nurpelin BN Levent Serkan S Çevi K Ulviye Acar UA Ilgin Sinem S Yurttaş Leyla L Özkay Yusuf Y Karaburun Ahmet Cagri AC Kaplancikli Zafer Asım ZA Gundogdu-Karaburun Nalan N

ACS omega 20240229 10

In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new compounds containing thiazolylhydrazone groups were synthesized. The structures of the obtained compounds were elucidated by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and high-resolution mass spectrometry (HRMS) methods. The inhibitory effects of the final compounds on MAO enzymes were investigated by means of in vitro methods. In add ...[more]

PMID: 38496951

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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.

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Design, Synthesis, and Biological Effect Studies of Novel Benzofuran-Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors.

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Design, Synthesis, and Biological Effect Studies of Novel Benzofuran-Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors.

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