Tian-Qi Mao, Qiu-Qin He, Wen-Xue Chen, Gang-Feng Tang, Fen-Er Chen, Erik De Clercq, Dirk Daelemans and Christophe Pannecouque Pages 6982 - 6987 ( 6 )
Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring. The biological results indicated that most of these hybrids could inhibit wt HIV-1 replication at nanomolar level ranging from 0.088 to 0.0096 μM. The most promising hybrid 5c displayed a significant EC50 value of 0.0096 μM against HIV-1 IIIB and of 0.98 μM against K103N/Y181C. Further docking studies revealed that these hybrids could be well located in the hydrophobic NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid scaffold in the molecules. These promising results suggested a high potential to further develop these hybrids as next-generation NNRTIs with improved antiviral efficacy and resistance profile.
Diarylpyrimidine, quinolone, hybrids, HIV-1 reverse transcriptase, anti-HIV, K103N/Y181C.
, Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of, , , Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of