Chagas Disease Drug Discovery: Multiparametric Lead Optimization against Trypanosoma cruzi in Acylaminobenzothiazole Series
Chagas Disease Drug Discovery: Multiparametric Lead Optimization against Trypanosoma cruzi in Acylaminobenzothiazole Series
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DOI：
10.1021/acs.jmedchem.9b01429
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发表时间：
2019-11-28
影响因子：
7.3
通讯作者：
Courtemanche, Gilles
中科院分区：
文献类型：
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作者：
Fleau, Charlotte;Padilla, Angel;Courtemanche, Gilles
酰氨基苯并噻唑HITS被确定为克氏锥虫复制的潜在抑制剂，克氏锥虫是一种导致恰加斯病的寄生虫。我们选择化合物1进行先导优化，旨在并行提高其抗T.CRUZI活性(IC_(50)=0.63µM)及其人体代谢稳定性(人体清除量=9.57毫升/分钟/克)合成了39个1的类似物，并进行了体外实验。我们建立了多参数结构-活性关系，允许优化抗寄生虫活性、物理化学参数和ADME性质。我们确定化合物50是一种高级先导化合物，具有更好的抗T抗体。体外CRUZI活性(IC_(50)=0.079µM)和增强的代谢稳定性(人体清除量=0.41mL/分钟/g)和口服给药途径的机会。经过耐受性评估，50例显示出良好的体内疗效。
Acylaminobenzothiazole hits were identified as potential inhibitors of Trypanosoma cruzi replication, a parasite responsible for Chagas disease. We selected compound 1 for lead optimization, aiming to improve in parallel its anti-T. cruzi activity (IC50 = 0.63 mu M) and its human metabolic stability (human clearance = 9.57 mL/min/g). A total of 39 analogues of 1 were synthesized and tested in vitro. We established a multiparametric structure-activity relationship, allowing optimization of antiparasite activity, physicochemical parameters, and ADME properties. We identified compound 50 as an advanced lead with an improved anti-T. cruzi activity in vitro (IC50 = 0.079 mu M) and an enhanced metabolic stability (human clearance = 0.41 mL/min/g) and opportunity for the oral route of administration. After tolerability assessment, 50 demonstrated a promising in vivo efficacy.