A. Design, synthesis, and anti-tubercular activity of leningosterol and its derivatives B. design, synthesis, and anti-Infective activity of isothiocyanate and isoselenocyanate-functionalized Amphilectane Diterpenes

Abstract

Saringosterol (1.22), a sterol isolated from the brown algae Sargassum ringgoldianum and Lessonia nigrescens, is a potent anti-tubercular agent with a minimum inhibitory concentration (MIC) of 0.25 µg/mL and low cytotoxicity towards the Vero cell line. However, its pharmacokinetic properties are hampered by its limited aqueous solubility. On the other hand, abeo-sterols, a sub-group of sterols, are also promising anti-tubercular agents. A small library of these compounds prepared by Rodríguez and co-workers suggests that the abeo-steroidal moiety is responsible for the activity. Based on these observations we designed a new molecule, named by us as leningosterol (2.1), which combines the structural features of abeo-sterols with those of saringosterol (1.22).

A synthetic strategy to access leningosterol (2.1) has been developed using 3ß-hydroxy-5-cholenic acid as the starting material. A Weinreb amide, ozonolysis, aldol addition, and organometallic alkylations were the key steps during the synthesis. Leningosterol (2.1) was finally obtained in ten steps with an overall yield of 7%. Surprisingly, leningosterol (2.1) exhibited only a moderate MIC of 20 µg/mL against Mycobacterium tuberculosis.

Fifteen derivatives were synthesized and evaluated for anti-tubercular activity in this research. Structure activity relationship (SAR) studies were performed to determine the influence of same substituents at C-24 on the anti-tubercular potency. Furthermore, the aldehyde functionality at C-6 and the 5,7-alkene moiety were modified as part of our efforts to optimize potency. MIC values ranged from 4.3 to >128 µg/mL with compound 3.14 being the most active

In another project, the marine natural product (–)-8,15-diisocyano-11(20)-amphilectene, isolated from the Caribbean sponge Svenzea flava, was used as scaffold to synthetize five new products, all of which were tested in vitro against laboratory strains of Plasmodium falciparum and Mycobacterium tuberculosis. The scaffold along with its isothio- and isoselenocyanate analogs displayed low to sub-micro molar (0.0012–11.7669 µM) anti-plasmodial activity with the best derivative, diisoselenocyanate (4.32), showing an IC[subscript 50] value of 0.0025 µM against a drug-sensitive strain 3D7. Of the compounds assayed against M. tuberculosis H[subscript 37]Rv, compound 4.35 was found to be the most active, with a MIC of 2.1µM.