Structure-based Design,Synthesis And Biological Evaluation Of Novel Diary Lpyridines HIV-1 NNRTIs

Human immunodeficiency virus type 1(HIV-1)is the main pathogen of AIDS.Reverse transcriptase(RT)has been considered as an ideal target for anti-AIDS drugs due to the vital role in the HIV-1 reverse transcription.Non-nucleoside reverse transcriptase inhibitors(NNRTIs)have become an important part of highly active antiretroviral therapy(HAART)owing to their potent antiviral activity and low cytotoxicity.Whereas,drug resistance and adverse effects brought by long-term treatment severely limit their clinical use.Therefore,these challenges promote us to develop novel NNRTIs with improved resistance profile and less toxicity.With the rapid development of structural biology,a large number of co-crystal structures of HIV-1 RT/NNRTIs complexes were well analyzed,providing useful information for rational design of anti-HIV drugs.In recent years,the optimization of DAPY analogues according to the "four-point pharmacophore" model was mainly concentrated on the tolerant region I and II,while the hydrogen bonding domain was also worth exploring for the key role to generate additional interaction with K101 in NNIBP.Based on the "four-point pharmacophore" model,ETR,K-5a2 and HBS-11c were used as lead compound,the core ring and right wing were modified by structural diversity to explore hydrogen bonding domain,tolerant region Ⅰ and tolerant region Ⅱ.A total of 24 novel compounds were designed and synthesized with the strategies of bioisosterism and molecular hybridization,in order to improve anti-HIV-1 activity,drug resistance profile and drug-like properties.The target compounds were screened for their biological activity against wild-type and mutant HIV-1 strains in MT-4 cells with the MTT method.Most of them showed potent activity to wild-type HIV-1.Among them,Ⅰ-3b,Ⅰ-6b,Ⅰ-6c,Ⅱ-3b,Ⅱ-6a,Ⅱ-6b,Ⅱ-6c and Ⅲ-6c exhibited higher potency with EC50 values ranging from 3.87 to 8.32 nM,which were comparable to that of the reference drug ETR(EC50=3.22 nM).Furthermore,compound Ⅰ-6b maintained sub-micromolar to nanomolar inhibitory activity against a panel of NNRTI-resistant mutations(EC50=9.37-171 nM),being comparable to that of EFV(EC50=6.34-890 nM).In addition,the target compounds were evaluated for their inhibitory activity to WT HIV-1 RT using the ELISA method.The result demonstrated that most of compound displayed strong enzyme inhibitory activity with IC50 values of 0.094-0.697 μM,which were superior to that of NVP(IC50=1.94 μM),indicating that the target of these novel compounds was RT.Moreover,the molecular docking studies showed that the cyano group substituted at the C-3 of the central ring forms a direct hydrogen bond with K101 in wild-type and mutant RT strains,which may contribute to the potent activity of represent compounds.Besides,compounds I-6b、II-6a and III-6c were evaluated for their water solubility at different pH values,and all of them exhibited enhanced solubility at pH 7.0 and pH 7.4 compared to that of ETR.In summary,with ETR,K-5a2 and HBS-11c as leads,24 novel diarylpyridines were designed as novel NNRTIs.The in vitro activity results demonstrated that several compounds possessing excellent anti-HIV-1 activity.Moreover,the structure-activity relationship and molecular simulation have been conducted to provide valuable reference for developing new generation of NNRTIs with higher activity and favorable druggability.