Sacubitril‐Based Urea and Thiourea Derivatives as Novel Inhibitors for Anti‐Tubercular against Dormant Tuberculosis

Abstract

In the present study, we have attempted to identify Sacubitril derivatives as lead compounds for dormant tuberculosis. A total of twenty‐one compounds belongs to a series of the Sacubitril derivatives 5(a – u) were synthesized using ( 2R , 4S )‐5‐([1,1′‐biphenyl]‐4‐yl)‐4‐(amino)‐2‐methylpentanoic acid ethyl ester hydrochloride with different isocyanates and isothiocyanates. All the compounds structures were determined by 1 H & 13 C NMR spectroscopy, mass spectrometry, and CHN analysis. Compound, 5 r , the structure confirmed by single‐crystal X‐ray diffraction analysis ( SXRD ). The newly synthesized compounds were screened for their in vitro antituberculosis activity (anti‐TB) against dormant Mycobacterium tuberculosis H37Rv (ATCC27294). Among the twenty‐one compounds, 5 p and 5 q were exhibited good potent anti‐TB activity compared to the standard drug Ethambutol. Further, the anti‐TB activities of the compounds ( 5 p and 5 q ) were evaluated against M. tuberculosis ( Mtb ) using the nutrient starvation model (NSM). Moreover, these two compounds, 5 p and 5 q have shown significant inhibition of growth of Mtb as compared to the control. To determine the toxicity nature, the potent anti‐TB active compounds were evaluated against RAW 264.7 cells. Further, the anti‐TB activities of all these compounds have shown a good correlation to their in‐silico molecular docking analysis by exhibiting strong interactions with the inhibitor Mur‐B.