Reddy Kummetha Indrasena, Srihari Konduri, Renuka Janupally, Sree Komanduri Shruthi, Chuppala Aruna, Jeankumar Variam Ullas, Sridevi Jonnalagadda Padma, Babu Kondra Sudhakar, Yogeeswari Perumal, Sriram Dharmarajan
Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515055, India.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, Hyderabad 500078, India.
Bioorg Med Chem. 2014 Dec 1;22(23):6552-6563. doi: 10.1016/j.bmc.2014.10.016.
A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand-protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 °C in differential scanning fluorimetric evaluations
通过八步反应，将噻唑氨基哌啶核心与脲侧链进行分子杂交，设计了一系列28个5-(哌嗪-1-基)苯并呋喃-2-羧酸乙酯和3-(哌嗪-1-基)苯并[d]异噻唑分子，并通过体外耻垢分枝杆菌（MS）GyrB ATP酶分析、结核分枝杆菌（MTB）DNA回旋酶超螺旋分析、抗结核活性、细胞毒性以及通过差示扫描荧光法进行的蛋白质-抑制剂相互作用分析对其进行筛选。此外，还应用Glide的高精度模式（XP）研究了最具活性的分子与MS DNA回旋酶B亚基活性位点的取向和配体-蛋白质相互作用。在所研究的化合物中，发现4-(苯并[d]异噻唑-3-基)-N-(4-氯苯基)哌嗪-1-甲酰胺（26）是最有前景的抑制剂，其对MS GyrB的IC50为1.77±0.23μM，对MTB DNA回旋酶的IC50为0.42±0.23，MTB的MIC为3.64μM，在100μM时对真核细胞无细胞毒性。此外，蛋白质-配体复合物的相互作用稳定，在差示扫描荧光分析中显示正移3.5℃。
