Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit–to–lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

异恶唑 化学 衍生化 化学型 抗细菌 组合化学 有机化学 结核分枝杆菌 色谱法 高效液相色谱法 肺结核 医学 病理 精油
作者
Miriam Girardini,Francesca Ferlenghi,Giannamaria Annunziato,Giulia Degiacomi,Bianca Papotti,Cinzia Marchi,Josè Camilla Sammartino,Sari Rasheed,Anna Contini,Maria Rosalia Pasca,Federica Vacondio,Joanna C. Evans,Thomas Dick,Rolf Müller,Gabriele Costantino,Marco Pieroni
出处
期刊:European journal of medicinal chemistry [Elsevier BV]
卷期号:245: 114916-114916 被引量:6
标识
DOI:10.1016/j.ejmech.2022.114916
摘要

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobacterium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure-Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l, escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains.
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