Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene3,2-pyrimidine derivatives as potent HIV-1 NNRTIs.
10.1016/j.apsb.2019.08.013
- Author:
Dongwei KANG
1
;
Da FENG
1
;
Tiziana GINEX
2
;
Jinmi ZOU
1
;
Fenju WEI
1
;
Tong ZHAO
1
;
Boshi HUANG
1
;
Yanying SUN
1
;
Samuel DESTA
1
;
Erik DE CLERCQ
3
;
Christophe PANNECOUQUE
3
;
Peng ZHAN
1
;
Xinyong LIU
1
Author Information
1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
2. Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy, Campus Torribera, Institute of Biomedicine and Institute of Theoretical and Computational Chemistry, University of Barcelona, Santa Coloma de Gramenet 08921, Spain.
3. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven B-3000, Belgium.
- Publication Type:Journal Article
- Keywords:
HIV-1;
Hydrophobic channel;
NNIBP;
NNRTIs;
Thiophene[3,2-d]pyrimidine
- From:
Acta Pharmaceutica Sinica B
2020;10(5):878-894
- CountryChina
- Language:English
-
Abstract:
In this report, a series of novel piperidine-substituted thiophene[3,2-]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 . 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 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC 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, 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 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
