Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives

Abstract

In the search for compounds active against human immunodeficiency virus (HIV), we have found that members of a novel series of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1, the main aetiological agent of AIDS, but not of HIV-2, or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 10(4)-10(5) times lower than the cytotoxic concentration. The unprecedented specificity of these compounds may be due to an interaction with a reverse transcriptase-associated process. By contrast, AZT (3'-azido-2',3'-dideoxythymidine), which is used for the treatment of AIDS, and DDC (2',3'-dideoxycytidine) and DDI (2',3'-dideoxyinosine), whose clinical application is being assessed, inhibit both HIV-1 and HIV-2 at concentrations that, depending on the cell systems, are 2 to 4 orders of magnitude below their cytotoxic concentration. TIBO-derivatives are new chemicals unrelated to any other antiviral agents. We believe that they are the most specific and potent inhibitors of HIV-1 replication studied so far.

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

“…(Fig. 1) has been described by Pauwels et al (1990). For HEPT and its derivative E-EPU [5-ethyl-l-ethoxymethyl-6-(phenylthio)uracil] (Fig.…”

“…We have now studied various SIV strains for their susceptibility to inhibition by the novel HIV-l-specific reverse transcriptase (RT) inhibitors tetrahydro-imidazo [4,5, l-jk][ 1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and the 1-(2-hydroxyethoxymethyl)-6-(phenylthio)-thymine (HEPT) derivatives (Pauwels et al, 1990;Baba et al, 1991 ;Debyser et al, 1991). 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.…”

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

“…Various compounds have been shown to selectively inhibit the activity of this enzyme (1) Iriphosphates act as DNA chain terminators and suppress the enzyme activity (3). However, they interact not only with HIV-1 RT but also with other retroviral RTs (4,5) and even with cellular DNA polymerases (6). Thus, serious side effects are often associated with a long-term administration of these compounds (7).…”

“…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).…”

Synthesis of a Multifunctional Oxazolo[5,4-e][1,4]diazepine Skeleton

“…This skeleton has been applied in the development of cholecystokinin (CCK) receptor A and B antagonists, 2 opioid receptor ligands, 3 platelet-activating factor antagonists, 4 human immuno-deficiency virus transactivator Tat antagonists, 5 reverse transcriptase inhibitors, 6 and ras farnesyltransferase inhibitors. 7 During the past decade attention has also been diverted to the synthesis of 1,4-diazepinones with a fused heterocyclic system in place of the benzene ring 8,9 to explore the heterocycle for various biological applications.…”