Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase and the alkenyldiarylmethanes (ADAMs), a new series of compounds has been synthesized and evaluated for inhibition of HIV-1 replication. The modifications reported in this new series include primarily changes to the alkenyl chain. The most potent compound proved to be methyl 3',3' '-dibromo-4',4' '-dimethoxy-5',5' '-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (28), which displayed an EC(50) of 1.3 nM for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM 28 inhibited HIV-1 reverse transcriptase with an IC(50) of 0.3 microM. Mutations that conferred greater than 10-fold resistance to ADAM 28 clustered at residues Val 106, Val 179, Tyr 181, and Tyr 188. Results derived from this series indicate that ADAMs containing chlorines in the aromatic rings might bind to HIV-1 reverse transcriptase in a slightly different mode when compared with those analogues incorporating bromine in the aromatic rings.

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.…”

“…13 C NMR spectra were obtained at 75 MHz. 19 F NMR spectra were recorded at 282 MHz using trifluoroacetic acid in DMSO as the external standard. Chemical ionization mass spectra (CIMS) were determined using isobutane as the reagent gas.…”

“…[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 crude oil was purified by flash column chromatography using silica (50 g, 3 cm × 18 cm), with a gradient eluent from 0 to 10% ethyl acetate in hexanes. Like fractions were combined and solvent was removed in vacuo to yield an amorphous solid Methyl 3′,3′′-Difluoro-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (14). TiCl4/THF 1:2 complex (1.64 g, 4.9 mmol) and zinc dust (0.641 g, 9.8 mmol) were heated under reflux in THF (16 mL) under an argon atmosphere for 1 h. Di[3-fluoro-4-methoxy-5-(methoxycarbonyl)phenyl] ketone (52, 0.387 g, 0.98 mmol) and methyl 5-oxopentanoate 27 (67, 0.255 g, 2.0 mmol) were taken up in THF (16 mL) and were added in one portion via cannula under argon pressure to the refluxing mixture.…”

Synthesis and Anti-HIV Activity of New Metabolically Stable Alkenyldiarylmethane Non-Nucleoside Reverse Transcriptase Inhibitors Incorporating N-Methoxy Imidoyl Halide and 1,2,4-Oxadiazole Systems

“…[3][4][5][6][7][8][9][10][11][12][13][14] In addition, ADAMs have displayed synergistic activity with AZT and enhanced activity when tested against AZT-resistant strains of HIV-1. 4,5,7,8 Certain ADAMs, for example compounds 1 and 2, have been found to inhibit HIV-1 RT and the cytopathic effect of HIV-1 in cell culture.…”