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

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 microM). 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 microM). 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 microM), while the levo isomer was more than 60-fold less active.