New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3"-dichloro-4',4"-dimethoxy-5', 5"-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 microM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

“…These carbonyl groups are present in ester, amide, or carbamate functional groups, and it is proposed that they might act as hydrogen bond acceptors from the backbone amide of Lys101 of reverse transcriptase ( Figure 1). 13,19 In Figure 1, the originally proposed bifurcated hydrogen bond involving the side chain ester carbonyl of ADAM 17 with the terminal amino group of Lys103 and the backbone NH of Lys101 has been modified to include bonding between the backbone NH of Lys101 and the ester carbonyl only, which seems to be more consistent with the present observation of resilience of ADAMs 15, 17, 19, and 21 to the K103E mutation (Table 3). 13,19 As judged from the activities displayed by 36 and 37, the thioesters are not as active as the corresponding esters 15 and 19, amide 28, or carbamates 40 and 43.…”

“…Compounds 1, 3, 5, 6, 15, and 17 were synthesized as previously described. 11,13,14 3′,3′′-Difluoro-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-1,1-diphenyl-1-heptene (2). TiCl4/THF 1:2 complex (2.05 g, 6.15 mmol) and zinc dust (0.804 g, 12.3 mmol) were heated at reflux in THF (20 mL) under an argon atmosphere for 1 h. Di[3-fluoro-4-methoxy-5-(methoxycarbonyl)phenyl] ketone (52, 0.486 g, 1.23 mmol) and hexanal (0.22 mL, 1.85 mmol) were taken up in THF (20 mL) and were added in one portion via cannula under argon pressure to the refluxing mixture.…”

“…[15][16][17][18] The syntheses of 1, 13 2, 19 3, 11 5, 13 6, 13 14, 14 15, 13 and 17 19 were carried out as previously reported and are included in Table 1 for comparison purposes. The required benzophenones 51, 13 52, 19 53, 21 55, 11 and 56 13 were prepared as previously described, and the remaining two benzophenones 54 and 57 were synthesized as outlined in Schemes 1 and 2. Alkylation of both phenoxide anions and both carboxylates derived from the substituted diphenylmethane 58 22 with dimethyl sulfate, using potassium carbonate in acetone as the base, afforded intermediate 59, which was then oxidized to the desired benzophenone 54 with chromium trioxide in acetic acid (Scheme 1).…”

“…The organic layers were combined and dried over Na2SO4 and then evaporated to give a light-yellow residue. The residue was purified by flash chromatography (silica gel 50 g, solvent hexanes/ethyl acetate 2:1, v/v) to afford a colorless oil (75 mg, 20%): 1 91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.64 (s, 3 H), 3.28 (dt, J ) 6.35 and 6.31 Hz, 2 H), 2.30 (dt, J ) 7.08 and 6.88 Hz, 2 H); 13 4-(N-Methyloxycarbonyl)amino-3′,3′′-dimethyl-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-1,1-diphenylbutene (41). TiCl4/THF 1:2 complex (965 mg, 2.89 mmol) was added to a stirred suspension of zinc dust (378 mg, 5.78 mmol) in dry THF (8 mL).…”

“…Hz, 2 H), 1.81 (m, 2 H), 1.23 (t, J ) 7 33. Hz, 3 H);13 C NMR (CDCl3) δ 194.37, 161.15, 161.06, 160.85, 150.46, 149.77, 133.68, 133.41, 131.67, 130.50, 130.35, 129.55, 127.81, 127.18, 126.34, 125.28, 125.14, 124.84, 123.43, 122.19, 122.03, 57.30, 47.84, 38.61, 35.12, 24.34, 20.65, 18.58, 10.02; CIMS (MH + ) m/z 554. Anal.…”