Synthesis, Characterization, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL

Current computer-aided drug design Pub Date : 2023-01-01 DOI:10.2174/1573409919666221227091735

Vijay J Desale, Suraj N Mali, Bapu R Thorat, Ramesh S Yamgar, Swapnali V Dharanguttikar, Vyankatesh R Dharanguttikar, Samir Chtita, Mozaniel Oliveira, Jorddy Neves Cruz

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引用次数: 1

Abstract

Background: Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions.

Objectives: Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as ¹H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay.

Results: Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e).

Conclusion: Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.

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4-[(取代苄基)氨基]苯并肼及其腙作为酰基辅酶a羧化酶AccD5抑制剂的合成、表征、'ADMET-SAR'预测、DPPH测定和抗分枝杆菌研究

背景:腙类衍生物具有多种生物活性，如抗结核、抗菌、抗真菌、抗癌、抗炎、抗病毒和抗原虫作用。目的:腙类化合物含有与羰基连接的亚甲胺(- nhn =CH-)基团，被认为具有多种药物应用。它们有助于合成不同的五元杂环体系，如恶二唑、三唑等。方法:以4-氨基苯甲酸衍生物为原料，合成了多种肼/腙类化合物。采用核磁共振(1H-NMR)、傅里叶变换红外光谱(FT-IR)、气相色谱-质谱(GC-MS)等多种光谱方法对新合成的9个化合物(6a-6d和8a- 8e)的结构进行了进一步表征。此外，还使用Glide模块对酰基辅酶a羧化酶AccD5 (PDB ID: 2A7S)进行了分子对接分析，其结合分数比标准药物高。采用Alamar-Blue药敏试验(MABA)评价了所有肼和腙(6a-6d和8a-8e)对结核分枝杆菌H37 RV菌株的抗结核活性。活性以最小抑制浓度(MIC)表示，单位为μg/mL。采用DPPH法测定其抗氧化活性。结果:我们的研究结果显示了高度令人鼓舞的体外结果(MABA测定，MIC: 1.2 μg/mL)，并描绘了良好的抗细菌活性。抗氧化结果显示对DPPH有中等到良好的抑制作用。我们的计算机ADMET分析进一步表明，合成的类似物(6a-6d和8a-8e)具有良好的药代动力学和无毒特征。结论:我们的研究结果表明，腙/肼是未来开发更有效和更安全的抗结核药物的潜在候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current computer-aided drug design 医学-计算机：跨学科应用

CiteScore

3.70

自引率

5.90%

发文量

审稿时长

>12 weeks

期刊介绍： Aims & Scope Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, theoretical chemistry; computational chemistry; computer and molecular graphics; molecular modeling; protein engineering; drug design; expert systems; general structure-property relationships; molecular dynamics; chemical database development and usage etc., providing excellent rationales for drug development.