Structural Modifications of Diarylpyrimidine-quinolone Hybrids as Potent HIV-1 NNRTIs with an Improved Drug Resistance Profile

Title:Structural Modifications of Diarylpyrimidine-quinolone Hybrids as Potent HIV-1 NNRTIs with an Improved Drug Resistance Profile

Volume: 22 Issue: 46

Author(s): Tian-Qi Mao, Qiu-Qin He, Wen-Xue Chen, Gang-Feng Tang, Fen-Er Chen, Erik De Clercq, Dirk Daelemans and Christophe Pannecouque

Affiliation:

Keywords: Diarylpyrimidine, quinolone, hybrids, HIV-1 reverse transcriptase, anti-HIV, K103N/Y181C.

Abstract: 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 III_B 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.

Cite this article as:

Mao Tian-Qi, He Qiu-Qin, Chen Wen-Xue, Tang Gang-Feng, Chen Fen-Er, Clercq De Erik, Daelemans Dirk and Pannecouque Christophe, Structural Modifications of Diarylpyrimidine-quinolone Hybrids as Potent HIV-1 NNRTIs with an Improved Drug Resistance Profile, Current Pharmaceutical Design 2016; 22 (46) . https://dx.doi.org/10.2174/1381612823666161122125657