Noor Tahira, Schultz Daniel C, Seabra Gustavo, Zhai Yuting, Jeong Kwangcheol Casey, Bokhari Saleem Ahmed, Qureshi Fahim Ashraf, Siddiqi Abdul Rauf, Li Chenglong
Department of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad 45550, Pakistan.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
EXCLI J. 2025 Apr 1;24:527-538. doi: 10.17179/excli2024-8118. eCollection 2025.
Antimicrobial resistance is a growing public health threat worldwide, and the current drug development pipeline has thus far been inadequate in addressing this impending crisis. Further research into antibiotic agents, both existing and novel, is therefore paramount for identifying suitable candidates to combat antibiotic-resistant pathogens. Sulfonamides, the first class of synthetic antibiotics, target dihydropteroate synthase (DHPS), a key bacterial enzyme. While this class of antibiotics has historically demonstrated great utility, their use has diminished due to resistance and undesired side effects. In the present study, we synthesized a selection of four sulfonamide analogues (, , and ), validated their structures through NMR spectroscopy, and evaluated their inhibitory potential through computational docking and MIC assays against four bacterial strains: ATCC 25923, ATCC 27853, ATCC 35401 and ATCC 6633. Each compound exhibited antibacterial activity; demonstrated the most potent activity, with an MIC of 32, 16, 16, and 16 µg/mL against aforementioned strains, respectively. , and , on the other hand, exhibited moderate activity against and (MIC = 128 µg/mL each) and low activity against and (MIC = 256 µg/mL each). Molecular docking studies indicated that captures multiple hydrogen bonding, ionic, and π-π interactions with key binding pocket residues of DHPS, and also demonstrated superior predicted drug-likeness in ADMET studies compared to other compounds. is therefore a favorable starting point for further optimization.
抗菌耐药性是全球日益严重的公共卫生威胁，而目前的药物研发渠道迄今在应对这一迫在眉睫的危机方面一直不够充分。因此，对现有和新型抗生素药物进行进一步研究对于确定对抗耐药病原体的合适候选药物至关重要。磺胺类药物是第一类合成抗生素，作用于二氢蝶酸合酶（DHPS），这是一种关键的细菌酶。虽然这类抗生素在历史上已证明具有很大的效用，但由于耐药性和不良副作用，其使用已有所减少。在本研究中，我们合成了四种磺胺类类似物（、、和），通过核磁共振光谱验证了它们的结构，并通过计算对接和针对四种细菌菌株的最低抑菌浓度（MIC）测定评估了它们的抑制潜力：金黄色葡萄球菌ATCC 25923、大肠杆菌ATCC 27853、肺炎克雷伯菌ATCC 35401和铜绿假单胞菌ATCC 6633。每种化合物都表现出抗菌活性；表现出最强的活性，对上述菌株的MIC分别为32、16、16和16 μg/mL。另一方面，、和对金黄色葡萄球菌和大肠杆菌表现出中等活性（MIC均为128 μg/mL），对肺炎克雷伯菌和铜绿假单胞菌表现出低活性（MIC均为256 μg/mL）。分子对接研究表明，与DHPS的关键结合口袋残基捕获了多个氢键、离子和π-π相互作用，并且在ADMET研究中与其他化合物相比还表现出更优异的预测类药性。因此，是进一步优化的良好起点。
