Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
Int J Mol Sci. 2021 Feb 28;22(5):2427. doi: 10.3390/ijms22052427.
The Centers for Disease Control and Prevention (CDC) recognizes as an urgent-threat Gram-negative bacterial pathogen. Additionally, resistance to frontline treatment (dual therapy with azithromycin and ceftriaxone) has led to the emergence of multidrug-resistant , which has caused a global health crisis. The drug pipeline for has been severely lacking as new antibacterial agents have not been approved by the FDA in the last twenty years. Thus, there is a need for new chemical entities active against drug-resistant . Trifluoromethylsulfonyl (SOCF), trifluoromethylthio (SCF), and pentafluorosulfanyl (SF) containing -(1,3,4-oxadiazol-2-yl)benzamides are novel compounds with potent activities against Gram-positive bacterial pathogens. Here, we report the discovery of new -(1,3,4-oxadiazol-2-yl)benzamides ( and ) with highly potent activity against . Additionally, these new compounds were shown to have activity against clinically important Gram-positive bacteria, such as methicillin-resistant (MRSA), vancomycin-resistant enterococci (VRE), and (minimum inhibitory concentrations (MICs) as low as 0.25 µg/mL). Both compounds were highly tolerable to human cell lines. Moreover, showed an outstanding ability to permeate across the gastrointestinal tract, indicating it would have a high systemic absorption if used as an anti-gonococcal therapeutic.
疾病控制与预防中心（CDC）将淋病奈瑟菌视为一种紧急威胁的革兰氏阴性细菌病原体。此外，对一线治疗（阿奇霉素和头孢曲松联合治疗）的耐药性导致了多药耐药淋病奈瑟菌的出现，这引发了一场全球卫生危机。过去二十年，新的抗菌药物未获 FDA 批准，因此，针对耐药淋病奈瑟菌的药物研发管道严重匮乏。含三氟甲磺酰基（SOCF）、三氟甲硫基（SCF）和五氟硫基（SF）的 -(1,3,4-恶二唑-2-基)苯甲酰胺是一类新型化合物，对革兰氏阳性细菌病原体具有很强的活性。在这里，我们报告了一类新的 -(1,3,4-恶二唑-2-基)苯甲酰胺（和 ）的发现，它们对淋病奈瑟菌具有很强的活性。此外，这些新化合物对临床上重要的革兰氏阳性细菌也具有活性，如耐甲氧西林金黄色葡萄球菌（MRSA）、万古霉素耐药肠球菌（VRE）和化脓性链球菌（MIC 值低至 0.25 µg/mL）。这两种化合物对人细胞系都具有很高的耐受性。此外， 显示出出色的穿透胃肠道的能力，如果将其用作抗淋病奈瑟菌的治疗药物，它将具有很高的全身吸收能力。
