TY - JOUR
T1 - Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs
T2 - Design, synthesis and biological evaluation
AU - Feng, Da
AU - Wei, Fenju
AU - Sun, Yanying
AU - Sharma, Prem Prakash
AU - Zhang, Tao
AU - Lin, Hao
AU - Rathi, Brijesh
AU - De Clercq, Erik
AU - Pannecouque, Christophe
AU - Kang, Dongwei
AU - Zhan, Peng
AU - Liu, Xinyong
N1 - Publisher Copyright:
© 2021
PY - 2021/12
Y1 - 2021/12
N2 - Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside 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 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC50) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC50 value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC50 = 260 nmol/L) and comparable to that of ETR (EC50 = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC50) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.
AB - Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside 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 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC50) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC50 value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC50 = 260 nmol/L) and comparable to that of ETR (EC50 = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC50) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.
KW - Boronic acid
KW - DAPY
KW - HIV-1
KW - Molecular dynamics simulation
KW - NNIBP
KW - NNRTIs
UR - https://www.scopus.com/pages/publications/85102455539
U2 - 10.1016/j.cclet.2021.02.033
DO - 10.1016/j.cclet.2021.02.033
M3 - Article
AN - SCOPUS:85102455539
SN - 1001-8417
VL - 32
SP - 4053
EP - 4057
JO - Chinese Chemical Letters
JF - Chinese Chemical Letters
IS - 12
ER -