Design,Synthesis And Biological Evaluation Of CH(CN)-Diarylpyrimidines

HIV-1 non-nucleoside reverse transcriptase inhibitors?NNRTIs?are key components of highly active antiretroviral therapy?HAART?for treating acquired immune deficiency syndrome?AIDS?.Over the past decades,more than fifty structurally diverse classes of compounds have been reported as NNRTIs,which can be divided into the following categories according to their structures:TIBO?tetrahydroimidazobenzodiazepinone?,?-APA??-anilinophenylacetamide?,ITU?iminothiourea?,DABO?dihydro-alkoxy-benzyl-oxopyrimidine?,DATA?diaryltriazine?,DAPY?diarylpyrimidine?,etc.Diarylpyrimidine?DAPY?derivatives are second-generation NNRTIs with remarkable anti-HIV-1 activity and favorable pharmacological properties.Two representative DAPY analogues,etravirine?ETR?and rilpivirine?RPV?,were successfully approved by US Food and Drug Administration?FDA?and have been widely used in the clinic.In spite of their high antiviral activity,they have some issues such as high toxicity,poor water solubility,and low bioavailability.Thus,further optimizations of DAPYs is still the research focus in medicinal chemistry comminity.Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors.Herein,CH?CN?-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH?CN?-DABOs onto the etravirine?ETR?.Twenty four CH?CN?-DAPYs were synthesized and the activity against HIV-1 in MT-4 cell and the activity against the reverse transcriptase were evaluated.Compounds A5 exhibited promising activity against wild-type?WT?HIV-1.Further optimizations obtained compounds B6(EC₅₀=0.006?M)and B8(EC₅₀=0.008?M),which showed single-digit nanomolar potency against WT HIV-1.Moreover,these two compounds had EC₅₀ values of 0.06 and 0.08?M toward the K103N mutant,respectively.The preliminary structure–activity relationship?SAR?was concluded:?1?The2-position of 4-cyanophenyl was the most preferred position to improve antiviral activity;?2?A methyl group at the C5-position?R¹?of the pyrimidine core could increase the anti-HIV-1 activity.The above information might be helpful to further DAPY optimizations.The target products were confirmed by ¹H-NMR,¹³C-NMR and MS.