N-isopropyl-(4-methoxy-3-difluoromethyl)cinnamoyl amide targets mycobacterial MmpL3

European Journal of Medicinal Chemistry Reports Pub Date : 2024-07-11 DOI:10.1016/j.ejmcr.2024.100188

Mario D. Martínez , Liliana Rondón , Lisandro Ronconi , Mariano Prado Acosta , Agostina Crotta Asis , Gabriela Gago , Florencia Di Salvo , Gerardo Burton , Fernando Durán , Mariana Piuri

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Abstract

Mycobacterial infections still need new and more efficient drugs. In the present work we developed a new and simpler protocol for the synthesis of N-isopropyl-(4-methoxy-3-difluoromethyl)cinnamoyl amide, here named as 3M99F1, a promising candidate for mycobacterial growth inhibition. Using whole genome sequencing of 3M99F1 resistant strains we were able to identify Mycobacterial membrane protein Large 3 (MmpL3) as the target for this compound. MmpL3 inhibition by 3M99F1 was further confirmed by lipid analysis of Mycobacteria in the presence and absence of the drug. MmpL3 is well conserved in Mycobacteria, including atypical or NTM (non-tuberculous mycobacteria) and other Actinobacteria, but it is not present in humans, encouraging the development of new inhibitors using 3M99F1 as scaffold.

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N-异丙基-(4-甲氧基-3-二氟甲基)肉桂酰酰胺靶向分枝杆菌 MmpL3

霉菌感染仍然需要更有效的新药。在本研究中，我们开发了一种新的、更简单的 N-异丙基-(4-甲氧基-3-二氟甲基)肉桂酰酰胺的合成方法，在此命名为 3M99F1，它是一种有希望抑制分枝杆菌生长的候选药物。通过对耐受 3M99F1 的菌株进行全基因组测序，我们确定分枝杆菌膜蛋白大 3（MmpL3）是该化合物的靶标。通过对存在和不存在该药物的分枝杆菌进行脂质分析，进一步证实了 3M99F1 对 MmpL3 的抑制作用。MmpL3 在分枝杆菌（包括非典型或 NTM（非结核分枝杆菌）和其他放线菌）中有很好的保守性，但在人类中并不存在，这促使人们以 3M99F1 为支架开发新的抑制剂。

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来源期刊

European Journal of Medicinal Chemistry Reports

CiteScore

4.50

自引率

0.00%

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