Ommi Ojaswitha, Naiyaz Ahmad Mohammad, Gajula Siva Nageswara Rao, Wanjari Parita, Sau Shashikanta, Agnivesh Puja Kumari, Sahoo Santosh Kumar, Kalia Nitin Pal, Sonti Rajesh, Nanduri Srinivas, Dasgupta Arunava, Chopra Sidharth, Yaddanapudi Venkata Madhavi
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER) Balanagar Hyderabad 500037 Telangana India
Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute Sector 10, Jankipuram Extension, Sitapur Road Lucknow 226031 UP India.
RSC Med Chem. 2023 May 10;14(7):1296-1308. doi: 10.1039/d3md00079f. eCollection 2023 Jul 20.
The urgent development of newer alternatives has been deemed a panacea for tackling emerging antimicrobial resistance effectively. Herein, we report the design, synthesis, and biological evaluation of 1,3-diaryl substituted pyrazole-based urea and thiourea derivatives as antimicrobial agents. Preliminary screening results revealed that compound 7a (3,4-dichlorophenyl derivative) exhibited potent activity against (MIC = 0.25 μg mL) and compound 7j (2,4-difluorophenyl derivative) against (MIC = 1 μg mL). Compounds 7a and 7j were non-toxic to Vero cells with a favorable selectivity index of 40 and 200, respectively, and demonstrated good microsomal stability. Compound 7a exhibited equipotent activity (MIC = 0.25 μg mL) against various multidrug-resistant strains of , which include various strains of MRSA and VRSA, and elicited bacteriostatic properties. In an enzymatic assay, 7a effectively inhibited DNA gyrase supercoiling activity at a concentration of 8 times MIC. Further, molecular modeling studies suggested that compound 7a binds at the active site of DNA gyrase with good affinity.
开发更新的替代物的紧迫性被视为有效应对新出现的抗菌药物耐药性的万灵药。在此，我们报告了作为抗菌剂的1,3 - 二芳基取代吡唑基脲和硫脲衍生物的设计、合成及生物学评价。初步筛选结果表明，化合物7a（3,4 - 二氯苯基衍生物）对[具体菌株未提及]表现出强效活性（MIC = 0.25 μg/mL），化合物7j（2,4 - 二氟苯基衍生物）对[具体菌株未提及]表现出强效活性（MIC = 1 μg/mL）。化合物7a和7j对Vero细胞无毒，选择性指数分别为40和200，显示出良好的微粒体稳定性。化合物7a对包括各种耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素金黄色葡萄球菌（VRSA）菌株在内的各种多重耐药[具体菌株未提及]菌株表现出同等效力的活性（MIC = 0.25 μg/mL），并具有抑菌特性。在酶促试验中，7a在8倍MIC浓度下有效抑制DNA促旋酶超螺旋活性。此外，分子模拟研究表明化合物7a以良好的亲和力结合于DNA促旋酶的活性位点。
