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. 2005 Sep 22;48(19):6140-55.
doi: 10.1021/jm050452s.

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

Bo-Liang Deng  1 , Tracy L Hartman, Robert W Buckheit Jr, Christophe Pannecouque, Erik De Clercq, Phillip E Fanwick, Mark Cushman
Affiliations

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

Bo-Liang Deng et al. J Med Chem. .

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.

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Figures

Scheme 1<sup>a</sup>
Scheme 1a
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(PBut3)2, toluene, reflux.
Scheme 1<sup>a</sup>
Scheme 1a
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(PBut3)2, toluene, reflux.
Scheme 2<sup>a</sup>
Scheme 2a
aReagents and conditions: (a) Pd(PBut3)2, toluene, reflux.
Scheme 3<sup>a</sup>
Scheme 3a
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<sup>a</sup>
Scheme 4a
aReagents and conditions: (a) dimethyl sulfate, NaOH, TBAB, CH2Cl2-H2O, room temperature; (b) SO2Cl2, 50 °C; (c) Pd(PBut3)2, toluene, reflux.
Scheme 5<sup>a</sup>
Scheme 5a
aReagents and conditions: (a), N2HOH.HCl, KOH, MeOH; (b), carbonyldiimidazole, THF, reflux; (c), K2CO3, DMSO, CH3I.
Scheme 6<sup>a</sup>
Scheme 6a
aReagents and conditions: (a) Pd(PBut3)2, toluene, reflux.
None
None
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References

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