某些7-甲基-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮的合成、抗分枝杆菌活性评价及对接研究

Synthesis, Antimycobacterial Evaluation and Docking Studies of Some 7-Methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones.

作者信息

Malothu Narender, Kulandaivelu Umasankar, Jojula Malathi, Gunda Shravan Kumar, Akkinepally Raghuram Rao

机构信息

Medicinal Chemistry Division, University College of Pharmaceutical Sciences.

KL College of Pharmacy, KLEF Deemed to Be University.

出版信息

Chem Pharm Bull (Tokyo). 2018;66(10):923-931. doi: 10.1248/cpb.c17-00999.

DOI:10.1248/cpb.c17-00999

PMID:30270239

Abstract

Two series of 3-substituted-7-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5] thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7,2-dimethyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were synthesized and characterized using spectral data i.e., IR, H-, C-NMR, Mass and CHN elemental analyses. The synthesized compounds were evaluated for antibacterial activity against each of two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria and antimycobacterial activity screened against two strains i.e., Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid-resistant clinical sample. Further to validate potentiality of our design was analyzed using molecular docking studies by taking crystal structure of MTB pantothenate synthetase (MTB-PS) (PDB: 3IVX). In this study, some compounds 6k (Minimum Inhibitory Concentration (MIC): MIC-22 µM), 7d (MTB: MIC-22 µM) and 7k (MTB: MIC-11 µM) showed potential antibacterial and antimycobacterial activities.

摘要

合成了两个系列的3-取代-7-甲基-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮(6a-k)和3-取代-7,2-二甲基-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮(7a-k)衍生物，并利用光谱数据（即红外光谱、氢谱、碳谱、核磁共振谱、质谱和CHN元素分析）对其进行了表征。对合成的化合物针对两种革兰氏阳性菌（枯草芽孢杆菌和金黄色葡萄球菌）和两种革兰氏阴性菌（大肠杆菌和肺炎克雷伯菌）菌株进行了抗菌活性评估，并针对两种菌株（即结核分枝杆菌(MTB)H37Rv和一份耐异烟肼临床样本）进行了抗分枝杆菌活性筛选。此外，通过采用结核分枝杆菌泛酸合成酶(MTB-PS)（蛋白质数据银行编号：3IVX）的晶体结构进行分子对接研究，分析了我们设计的潜在性。在本研究中，一些化合物6k（最小抑菌浓度(MIC)：MIC-22 µM）、7d（对MTB：MIC-22 µM）和7k（对MTB：MIC-11 µM）显示出潜在的抗菌和抗分枝杆菌活性。