Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket

• Novel 6-substituted diarylpyridine derivatives were identified as HIV-1 inhibitors.
• If, Ia and IIa exhibited anti-HIV-1 (IIIB) activity with EC50 values of 35 nM, 43 nM and 41 nM, respectively.
• IIb inhibited the K103N mutation with an EC50 value of 49 nM.
• Preliminary SARs and molecular simulation of these new analogues were detailed.

The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib, IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail.

Through structure-based boisosteric replacement and molecular hybridization, a series of novel 6-substituted diarylpyridine derivatives were designed, synthesized and identified as inhibitors of wild-type HIV-1 strain and mutant strains in this paper.Figure optionsDownload as PowerPoint slide