Bicyclic ,-Acetals Containing Fused Cysteine-Amide System as New Heterocyclic Class Targeting Human Farnesyltransferase (FTase-h).

We report in this contribution the synthesis and in vitro biological evaluation of a novel class of chiral thiazoloisoindolinone scaffolds as potent inhibitors against human farnesyltransferase (FTase-h). The targeted products, sulfides (), sulfoxides (,), and sulfones (), containing up to three points of diversification, were obtained in a short-step sequence starting from the available and cost-effective -cysteine hydrochloride (), which is the source of N and S atoms and the chiral pool, and α-carbonyl benzoic acids (), which are isoindolinone precursors. Concisely, the key ester intermediates () provide (a) sulfide-amides () by solvent-free amidation, (b) sulfoxides (,) by selective -oxidation using NaIO, and (c) sulfones () by oxidation using MMPP. Finally, the obtained ,-acetal systems have shown promising inhibitory activities on FTase-h in the nanomolar range with excellent half maximal inhibitory concentration (IC) values up to 4.0 nanomolar (for example, 25.1 nM for sulfide , 67.3 nM for sulfone , and more interesting of 4.03 nM for sulfoxide ).