Tetrahydronaphthalene Lignan Compounds as Potent Anti-HIV Type 1 Agents

Abstract

Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lignan compounds was studied. THN derivatives prevented cell death caused by HIV-1 infection in MT-4 cells. They also inhibited giant cell formation by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells. The 50% effective concentration (ED50) of the most active compound, 1737 [5,6,7-trimethoxy-4-(3,4,5-trimethoxyphenyl)-1,3,3a,4,9,9a-hexahydron aphtho[2,3-c]thiophene], for inhibition of the cytopathic effects of HIV-1 infection ranged from 0.15 to 0.8 microM. The 50% cytotoxic concentration (CC50) of compound 1737 measured by the viability of MT-4 cells was 58 microM, indicating a selective index (CC50/ED50) of 70-400. Substitution of the phenyl ring with other structures markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. This resulted in compounds with a high selective index. One such compound was 1738 [7-methoxy5,6-methylenedioxy-4-(4-benzyloxy-3-methoxyphenyl)1,3,3a ,4,9,9a-hexahydronaphtho[2,3-c]thiophene], with a selective index higher than 770. The time-of-addition experiment indicated that these compounds acted at or near the reverse transcription step of the HIV-1 life cycle. THN derivatives inhibited HIV-1 reverse transcriptase (RT) in vitro at a concentration of 1 microM. Resistant viruses selected in the presence of THN derivatives showed some degree of cross-resistance to other nonnucleoside RT inhibitors, but not to the nucleoside RT inhibitor, AZT. THN derivatives failed to inhibit replication of pyridinone- and nevirapine-resistant HIV strains. However, compound 1737 inhibited replication of a TIBO-resistant strain more effectively than the wild-type HIV-1. Consistent with this result, compound 1737 also inhibited TIBO-resistant RT more effectively than the wild-type RT in vitro. These results suggested that THN derivatives interact with RT in a manner similar to but slightly different from that of other nonnucleoside HIV-1 RT inhibitors.

Combination of Candidate Microbicides Cellulose Acetate 1,2-Benzenedicarboxylate and UC781 Has Synergistic and Complementary Effects against Human Immunodeficiency Virus Type 1 Infection

“…For example, HIV-1 group O strains are de novo resistant to current NNRTIs (10), but these viruses are susceptible to CAPmediated antiviral activity (18). In the present study, we have demonstrated that CAP is effective in inhibiting infection by HIV-1 strain A17, which is highly resistant to UC781 and other NNRTIs (15,32), suggesting that CAP can be used for preventing sexual transmission of NNRTI-resistant variants. Furthermore, UC781 has no documented activity against other STD pathogens.…”

“…The HIV-1 strain A17, a variant of HIV-1 IIIB , is highly resistant to inhibition by NNRTIs, including pyridinone derivatives, BI-RG-587, and TIBO (tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2-one) compounds (15,32). Resistance results from mutations at amino acids 103 (K3N) and 181 (Y3C) in the viral RT.…”

Preclinical Evaluation of 1H-Benzylindole Derivatives as Novel Human Immunodeficiency Virus Integrase Strand Transfer Inhibitors

“…The origins of HIV-1(III B ), HIV-1(NL4.3) (1, 35), HIV-2(ROD), HIV-2(EHO) (4,36), and simian immunodeficiency virus strain MAC 251 [SIV(MAC 251 )] (7, 35) have been described previously. The compounds were evaluated for their inhibitory effects against the replication of a variety of mutant HIV strains in MT-4 cells, such as nucleoside reverse transcriptase inhibitor (NRTI)-resistant strains (24,27), nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant strains (15,31), a protease-resistant strain (5), an L-708,906-resistant strain (14), and an L-870,810-resistant strain (20). The MK-0518-resistant strain harboring G140S and Q148H (37,39) was generated through site-directed mutagenesis (26) Drug susceptibility assay.…”

Synthesis of Novel MKC-442 Analogues with Potent Activities against HIV-1

“…A 30 % inhibition of cell growth relative to control cultures was considered significant. The 50 % inhibitory concentration (IC 50 ) and the 50 % cytotoxic concentration (CC 50 ) were determined by interpolation from the plots of percent inhibition versus concentration of compound.The test for activity against HIV-1 was performed in MT-4 cell cultures infected with either wild-type HIV-1 (strain IIIB [26]) or NNRTI resistant HIV-1 (strain N119 [27], strain A17 [28,29].…”