Synthesis, anti-HIV activity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors

Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl, or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.

Scheme 1^a

^aReagents and conditions: (a) TsCl/pyridine, <20 °C; or KOH, THF-H₂O, room temperature; (b) 2-oxazolidinone, K₂CO₃, Bu₄NBr, toluene, reflux; (c) TMSCHN₂, MeOH, benzene, room temperature; or dimethyl sulfate, K₂CO₃, Bu₄NBr, CH₂Cl₂-H₂O, room temperature; (d) NaI, NaOH, NaOCl, 0–3 °C; (e) dimethyl sulfate, K₂CO₃, acetone, reflux; or dimethyl sulfate, NaOH, Bu₄NBr, CH₂Cl₂-H₂O, room temperature; (f) compound 25, PdCl₂(PPh₃)₂, Cu(I)I, Et₃N, THF, room temperature; (g) Bu₃SnH, Pd(PPh₃)₄, THF, room temperature; (h) compound 33, Pd₂(dba)₃, AsPh₃, CuI, NMP, 80 °C; (i) I₂, CH₂Cl₂, room temperature; (j) 3,4-dimethoxyphenylboronic acid, Pd(OAc)₂, 2-(di-t-butylphosphine)biphenyl, KF, THF, 60 °C; (k) compound 29, Pd(PBu^t₃)₂, toluene, reflux.

Scheme 1^a

^aReagents and conditions: (a) TsCl/pyridine, <20 °C; or KOH, THF-H₂O, room temperature; (b) 2-oxazolidinone, K₂CO₃, Bu₄NBr, toluene, reflux; (c) TMSCHN₂, MeOH, benzene, room temperature; or dimethyl sulfate, K₂CO₃, Bu₄NBr, CH₂Cl₂-H₂O, room temperature; (d) NaI, NaOH, NaOCl, 0–3 °C; (e) dimethyl sulfate, K₂CO₃, acetone, reflux; or dimethyl sulfate, NaOH, Bu₄NBr, CH₂Cl₂-H₂O, room temperature; (f) compound 25, PdCl₂(PPh₃)₂, Cu(I)I, Et₃N, THF, room temperature; (g) Bu₃SnH, Pd(PPh₃)₄, THF, room temperature; (h) compound 33, Pd₂(dba)₃, AsPh₃, CuI, NMP, 80 °C; (i) I₂, CH₂Cl₂, room temperature; (j) 3,4-dimethoxyphenylboronic acid, Pd(OAc)₂, 2-(di-t-butylphosphine)biphenyl, KF, THF, 60 °C; (k) compound 29, Pd(PBu^t₃)₂, toluene, reflux.

Scheme 2^a

^aReagents and conditions: (a) Pd(PBu^t₃)₂, toluene, reflux.

Scheme 3^a

^aReagents and conditions: (a) methyl 5-hexynoate, PdCl₂(PPh₃)₂, Cu(I)I, Et₃N, THF; (b) Bu₃SnH, Pd(PPh₃)₄, THF, room temperature; (c) for 45: dimethyl sulfate, NaOH, Bu₄NBr, CH₂Cl₂-H₂O, room temperature; for 46: dimethyl sulfate, potassium carbonate, acetone, reflux.

Scheme 4^a

^aReagents and conditions: (a) dimethyl sulfate, NaOH, TBAB, CH₂Cl₂-H₂O, room temperature; (b) SO₂Cl₂, 50 °C; (c) Pd(PBu^t₃)₂, toluene, reflux.

Scheme 5^a

^aReagents and conditions: (a), N₂HOH.HCl, KOH, MeOH; (b), carbonyldiimidazole, THF, reflux; (c), K₂CO₃, DMSO, CH₃I.

Scheme 6^a

^aReagents and conditions: (a) Pd(PBu^t₃)₂, toluene, reflux.