RESUMEN
A series of C-5 methyl substituted 4-arylthio- and 4-aryloxy-3-iodopyridin-2(1H)-ones has been synthesized as new pyridinone analogues for their evaluation as anti-HIV inhibitors. The optimization at the 5-position was developed through an efficient use of the key intermediates 5-ethoxycarbonyl- and 5-cyano-pyridin-2(1H)-ones (14 and 15). Biological studies revealed that several compounds show potent HIV-1 reverse transcriptase inhibitory properties, for example, compounds 93 and 99 are active at 0.6-50 nM against wild type HIV-1 and a panel of major simple/double HIV mutant strains.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH/efectos de los fármacos , Yodopiridonas/síntesis química , Yodopiridonas/farmacología , Fármacos Anti-VIH/química , Línea Celular , VIH/enzimología , VIH/genética , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Humanos , Concentración 50 Inhibidora , Yodopiridonas/química , Mutación , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
As part of a systematic SAR study on the 3-iodo-4-phenoxypyridinone 3 (IOPY) type non-nucleoside reverse transcriptase inhibitors, the analogues 4a-4z bearing different C-3 substituents were synthesized and evaluated for their anti-HIV activity against wild-type HIV-1 and four of the principal HIV mutant strains (K103N, Y181C, Y188L, and I100L). The results show that the 3-vinyl analogue 4j is the only compound which displays anti-HIV activity comparable to IOPY 3, and in this respect represents a possible back-up to this lead molecule.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Línea Celular , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Relación Estructura-ActividadRESUMEN
An efficient method for preparation of 4,6 or 5,6 disubstituted 3-aminopyridazines was easily carried out starting from easily available 4-bromo-pyridazine-3,6-dione, and using combination of both amination and Pd(0) cross-coupling reactions under microwave irradiation.
Asunto(s)
Técnicas Químicas Combinatorias , Piridazinas/química , Piridazinas/síntesis química , Catálisis , Microondas , Estructura Molecular , Paladio/químicaRESUMEN
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.