Synthesis and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones

Abstract

A series of novel thiazolidin-4-ones bearing a lipophilic adamantyl substituent at position 2, and versatile substituents on the nitrogen atom of the thiazolidine ring, were synthesized whereas several compounds exhibited a modest anti-HIV-1 activity, (±)-2-adamantan-1-yl-3-(4,6-dimethyl-pyridin-2-yl)-thiazolidin-4-one 22 was endowed with a remarkable antiviral potency (EC 50 = 0.35 μM). The adamantane moiety played an important role in the eventual antiviral activity of the compound. This compound behaved as a typical non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) with non-competitive inhibition against RT with respect to the substrate ( K i = 12 μM). Separation of the enantiomers via diastereoisomeric salts was performed for 22. X-ray studies enabled us to ascribe an S configuration to (−)-2-adamantan-1-yl-3-(4,6-dimethyl-pyridin-2-yl)-thiazolidin-4-one (−)- 22. Furthermore, it was found that the (+)- 22 isomer was predominantly responsible for the potent anti-HIV-1 activity (EC 50 value of 0.178 μM), while the levo isomer was more than 60-fold less active.