Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidinesubstituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs

In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

Design and optimization of piperidinesubstituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1NNRTIs: Design, synthesis and biological evaluation

Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.