Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases

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• 作者：Malothu Narender^a ; Bhandaru Jaswanth S.^a ; Kulandaivelu Umasankar^b ; Jojula Malathi^c ; Adidala Raghuram Reddy^c ; K.R. Umadevi^d ; A.V.N. Dusthackeer^d ; Kaki Venkat Rao^e ; Akkinepally Raghuram R.^a ; ^{raghumed@kakatiya.ac.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pyrido[4&prime ; 3&prime ; 4 ; 5]thieno(2 ; 3-d)pyrimidine-4-(3H)-one ; Antibacterial activity ; MIC ; LRP assay ; Mycobacterium tuberculosis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：836-840
• 全文大小：784 K

文摘

Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4&prime;,3&prime;:4,5]thieno[2,3-<em>dem>]pyrimidin-4(<em>3Hem>)-one (6a–k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4&prime;,3&prime;:4,5]thieno[2,3-<em>dem>]pyrimidin-4(<em>3Hem>)-one (7a–k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in <em>Mycobacterium tuberculosisem> (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (<em>Bacillus subtilisem> and <em>Staphylococcus aureusem>) and Gram-negative (<em>Escherichia coliem> and <em>Klebsiella pneumoniaeem>) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB<em>.em> The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15–73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC₅₀ <340 μM in LRP assay) and (MIC <9 μM in broth microdilution method).