Deciphering the anti-Mycobacterium tuberculosis activity of bioinspired lipidic alkynylcarbinols

This article reports the first in-depth structure-activity relationship investigation of the anti-Mycobacterium tuberculosis (Mtb) potential of falcarindiol, a representative natural acetylenic lipid found in medicinal herbs of various traditional pharmacopeias. Prompted by our previous work on bioinspired anticancer lipidic alkynylcarbinols, we implemented a chemistry-driven deconstruction-reconstruction approach. This led to a detailed analysis of the key structural elements required for an optimized balance between potent anti-mycobacterial activity and low cytotoxicity against mammalian cells. More than 40 synthetic falcarindiol analogues were prepared and evaluated, including individual stereoisomers thanks to a combined chromatographic and chemoenzymatic resolution strategy. Structural evolution guidelines for decoupling of the cytotoxic and anti-Mtb activities of falcarindiol were thus defined. This allowed to increase the level of activity and selectivity by one order of magnitude as compared to the parent natural product falcarindiol with an anti-Mtb minimum inhibitory concentration down to 0.3 μM and a selectivity index up to 242. Overall, this study identifies a new anti-Mtb pharmacophore and opens up prospects for the development of first-in-class anti-Mtb chemical series through the design of novel bio-inspired chemotypes that could fuel the anti-tuberculosis drug discovery and development pipelines.