Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity.

Abstract

Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyljamino}-5-ethyl-6methylpyridin-2(LH)-one (L-697,639) and 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methylJamino}-5-ethyl--methylpyridin-2(IH)-one (L-697,661) Infection with the human immunodeficiency virus type 1 (HIV-1) causes progressive destruction of the immune system, which ultimately results in AIDS. An essential step in the life cycle of HIV-1 is reverse transcription of the viral RNA genome to produce a double-stranded DNA copy. This process is mediated by the virally encoded reverse transcriptase (RT). Thus, RT is a potential therapeutic target and, indeed, nucleoside analog inhibitors of RT, such as 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI), are clinically effective drugs for treating HIV-1 infection (1, 2). However, their effectiveness is limited by toxicities, which may reflect inhibition of cellular polymerases and/or alteration of nucleoside pools, given that the nucleoside analogs are phosphorylated (in competition with natural nucleosides) to their active form by cellular kinases (3, 4). The emergence of AZT-resistant virus (5) further emphasizes the need to develop selective RT inhibitors that can be used either alone or in combination with nucleoside analogs. The development of specific RT inhibitors is the subject ofthis communication. (L-697,661) were synthesized by alkylation of 3-amino-5-ethyl-6-methylpyridin-2(1H)-one with either N-hydroxymethylphthalimide or the appropriate 2-halomethylbenzoxazole. Requisite aminopyridinone was obtained from condensation of 3-formyl-2-pentanone with nitroacetamide followed by catalytic reduction.Synthesis of ethylene derivative 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one (L-693,593) began with the condensation of 3-formyl-2-pentanone and cyanoacetamide to give 3-cyano-5-ethyl-6-methylpyridin-2(1H)-one. Reaction of this cyanopyridinone with POCl3 followed by methanolysis and reduction with diisobutylaluminum hydride led to 5-ethyl-2-methoxy-6-methylpyridine-3-carboxaldehyde. The aldehyde function was treated with trimethylsilyl cyanide, and the resulting cyanohydrin was reduced with lithium aluminum hydride to the amino alcohol. After conversion of the amino group to phthalimide, demethylation ofthe 2-methoxy group and alcohol dehydration was accomplished in one step by heating with pyridine hydrochloride. Catalytic reduction of the olefin formed yielded ethylene analog L-693,593. The structures of all pyridinones synthesized are consistent with their NMR spectra, and all compounds gave an acceptable combustion analysis (within 0.4%).H1V-1 RT Assays. rC-dG.

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

“…In previous studies it was found that TIBO and TIBOlike compounds inhibit HIV-1 RT non-competitively with respect to the natural substrate (Debyser et al, 1991;Goldman et al, 1991;Merluzzi et al, 1991). However, for HEPT itself, which is a relatively weak inhibitor of HIV-1 RT, we found a competitive type of inhibition (Debyser et al, 1992a).…”

“…In contrast to the classical RT inhibitors such as phosphonoformic acid (PFA) and 3'-azido-3'-deoxythymidine (AZT) 5'-triphosphate, TIBO and HEPT inhibit HIV-1 RT, but not HIV-2 RT. The more recently developed dipyridodiazepinones, pyridinones and bis(hetero-aryl)piperazines share this property (Merluzzi et al, 1990;Goldman et al, 1991;Romero et al, 1991). The HIV-l-specific RT inhibitors are ineffective not only against HIV-2 RT, but also against the RTs of avian myeloblastosis virus, Moloney murine leukaemia virus, SIV [from macaques (SlVmac)] and feline leukaemia virus (Merluzzi et al, 1990;Debyser et al, 1991;Goldman et al, 1991).…”

A novel anthranilic acid based multi-component strategy for expeditious synthesis of 4(3H)-quinazolinone N-nucleosides

“…[1][2] Recently quinazolinones have gained recognition as they exhibit anti-HIV activity. 6-Chloro-(4S)-cyclopropyl-3,4-dihydro-4(2-pyridyl)ethynylquinazolin-2(1H)-one 1, a novel structural class of non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT), displays synergistic inhibition of RT activity with AZT triphosphate.…”

Inhibitory effect of 4‐(2,6‐dichlorophenyl)‐1,2,5‐thiadiazol‐3‐yl‐N‐methyl, N‐ethylcarbamate on replication of human immunodeficiency virus type 1 and the mechanism of action

“…They include tetrahydroimidazo-[4,5,Ijk] [1,4]benzodiazepin-2(1H)-one and -thione (TIBO) (4), nevirapine (8), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives (9), ot-anilinophenylacetamide (t~-APA) derivatives (5), and pyridinone derivatives (10). All of these compounds are highly inhibitory to HIV-I RT but are totally inactive against other retroviral RTs, including HIV-2, or cellular DNA polymerases (4,10). We have recently found 4-(2,6-dichlorophenyl)-l,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives to be a novel class of HIV-1 inhibitors (11).…”