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Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives.
ACS Omega ( IF 3.7 ) Pub Date : 2018-03-14 , DOI: 10.1021/acsomega.7b02047 Meenakshi Jain 1 , C V Ravi P Reddy 1 , Moumita Halder 1 , Savita Singh 1 , Randheer Kumar 1 , Sagar Gajbe Wasudeo 1 , Prati Pal Singh 1 , Shabana I Khan 2 , Melissa R Jacob 2 , Babu L Tekwani 2 , Rahul Jain 1
ACS Omega ( IF 3.7 ) Pub Date : 2018-03-14 , DOI: 10.1021/acsomega.7b02047 Meenakshi Jain 1 , C V Ravi P Reddy 1 , Moumita Halder 1 , Savita Singh 1 , Randheer Kumar 1 , Sagar Gajbe Wasudeo 1 , Prati Pal Singh 1 , Shabana I Khan 2 , Melissa R Jacob 2 , Babu L Tekwani 2 , Rahul Jain 1
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In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5-alkoxy, 4-methyl, and 2-tert-butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC50 = 20-4760 ng/mL (drug-sensitive Plasmodium falciparum D6 strain) and IC50 = 22-4760 ng/mL (drug-resistant P. falciparum W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive Plasmodium berghei and at 50 mg/kg/day against multidrug-resistant Plasmodium yoelii nigeriensis infections in Swiss mice. The in vitro antileishmanial activities (IC50 = 0.84-5.0 μg/mL and IC90 = 1.95-7.0 μg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (Candida albicans-IC50 = 4.93-19.38 μg/mL; Candida glabrata-IC50 = 3.96-19.22 μg/mL; Candida krusei-IC50 = 2.89-18.95 μg/mL; Cryptococcus neoformans-IC50 = 0.67-18.64 μg/mL; and Aspergillus fumigatus-IC50 = 6.0-19.32 μg/mL) and antibacterial activities (Staphylococcus aureus-IC50 = 1.33-18.9 μg/mL; methicillin-resistant S. aureus-IC50 = 1.38-15.34 μg/mL; and Mycobacterium intracellulare-IC50 = 3.12-20 μg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials.
中文翻译：
8-喹啉胺及其氨基酸缀合物作为广谱抗感染剂的合成和生物学评价。
在寻找新出现的耐药寄生虫的治疗剂的过程中，新型 8-喹啉胺的合成已成为一种成功的化疗方法。我们报道了在喹啉骨架中带有5-烷氧基、4-甲基和2-叔丁基的8-喹啉胺及其作为广谱抗感染剂的氨基酸缀合物的合成。 8-喹啉胺表现出有效的体外抗疟活性[IC50 = 20-4760 ng/mL（药物敏感的恶性疟原虫D6菌株）和IC50 = 22-4760 ng/mL（耐药恶性疟原虫W2菌株）]。最有前途的类似物已经治愈了瑞士小鼠中的所有动物，每天 25 毫克/公斤/天，可治疗药物敏感的伯氏疟原虫；每天 50 毫克/公斤，可治疗多重耐药的约氏疟原虫感染。几种合成的 8-喹啉胺表现出与标准药物喷他脒相当的体外抗利什曼胺活性（IC50 = 0.84-5.0 μg/mL 和 IC90 = 1.95-7.0 μg/mL）。同时，非常有前景的抗真菌活性（白色念珠菌-IC50 = 4.93-19.38 μg/mL；光滑念珠菌-IC50 = 3.96-19.22 μg/mL；克柔念珠菌-IC50 = 2.89-18.95 μg/mL；新型隐球菌-IC50 = 0.67-18.64 μg/mL；烟曲霉-IC50 = 6.0-19.32 μg/mL）和抗菌活性（金黄色葡萄球菌-IC50 = 1.33-18.9 μg/mL；耐甲氧西林金黄色葡萄球菌-IC50 = 1.38-15.34 μg） /mL；并且还观察到胞内分枝杆菌-IC50 = 3.12-20μg/mL)。 8-喹啉胺均不表现出细胞毒性，因此是一类很有前景的抗寄生虫药和抗菌剂结构化合物。
更新日期：2018-03-14
中文翻译：
8-喹啉胺及其氨基酸缀合物作为广谱抗感染剂的合成和生物学评价。
在寻找新出现的耐药寄生虫的治疗剂的过程中，新型 8-喹啉胺的合成已成为一种成功的化疗方法。我们报道了在喹啉骨架中带有5-烷氧基、4-甲基和2-叔丁基的8-喹啉胺及其作为广谱抗感染剂的氨基酸缀合物的合成。 8-喹啉胺表现出有效的体外抗疟活性[IC50 = 20-4760 ng/mL（药物敏感的恶性疟原虫D6菌株）和IC50 = 22-4760 ng/mL（耐药恶性疟原虫W2菌株）]。最有前途的类似物已经治愈了瑞士小鼠中的所有动物，每天 25 毫克/公斤/天，可治疗药物敏感的伯氏疟原虫；每天 50 毫克/公斤，可治疗多重耐药的约氏疟原虫感染。几种合成的 8-喹啉胺表现出与标准药物喷他脒相当的体外抗利什曼胺活性（IC50 = 0.84-5.0 μg/mL 和 IC90 = 1.95-7.0 μg/mL）。同时，非常有前景的抗真菌活性（白色念珠菌-IC50 = 4.93-19.38 μg/mL；光滑念珠菌-IC50 = 3.96-19.22 μg/mL；克柔念珠菌-IC50 = 2.89-18.95 μg/mL；新型隐球菌-IC50 = 0.67-18.64 μg/mL；烟曲霉-IC50 = 6.0-19.32 μg/mL）和抗菌活性（金黄色葡萄球菌-IC50 = 1.33-18.9 μg/mL；耐甲氧西林金黄色葡萄球菌-IC50 = 1.38-15.34 μg） /mL；并且还观察到胞内分枝杆菌-IC50 = 3.12-20μg/mL)。 8-喹啉胺均不表现出细胞毒性，因此是一类很有前景的抗寄生虫药和抗菌剂结构化合物。
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