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.
Balzarini
Jan
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Orzeszko
Barbara
B
Maurin
Jan K
JK
Orzeszko
Andrzej
A
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D045162:Thiazolidinediones; D054303:HIV Reverse Transcriptase