Abstract：
A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-β (TGF-β). Compound 3n showed a non-significant deviation of lung TGF-β1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-β and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state.
摘要：
设计并合成了带有苯磺酰胺部分的新喹唑啉药效团文库。筛选化合物3a-n对八种多药耐药临床分离株的体外抗微生物活性。化合物3d和3n表现出突出的抗菌活性，特别是针对MRSA。在表现出相对的体外和体内安全性后，选择化合物3n以评估其抗炎活性,与布洛芬相比显示有希望的COX-2抑制活性。在免疫缺陷(照射)小鼠上进行体内实验性MRSA肺炎模型,以揭示化合物3n与阿奇霉素(AZ)相比的抗微生物和抗炎应答。用化合物3n(10和20mg/kg)以及AZ处理导致肺组织中细菌计数的显著减少,抑制血清C反应蛋白(CRP),肺白细胞介素-6（IL-6），髓过氧化物酶活性（MPO）和转化生长因子-β（TGF-β）。化合物3n显示肺TGF-β1与正常值的非显著偏差,这反过来控制了肺炎症状态并影响了组织病理学结果。3n的分子对接显示TGF-β和COX-2的活性位点内部有希望的相互作用。我们的发现提出了一种新的双目标喹唑啉苯磺酰胺衍生物3n，在免疫受损状态下具有治疗MRSA引起的肺炎的巨大潜力。
