Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles

Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.