1.Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene3,2-pyrimidine derivatives as potent HIV-1 NNRTIs.
Dongwei KANG ; Da FENG ; Tiziana GINEX ; Jinmi ZOU ; Fenju WEI ; Tong ZHAO ; Boshi HUANG ; Yanying SUN ; Samuel DESTA ; Erik DE CLERCQ ; Christophe PANNECOUQUE ; Peng ZHAN ; Xinyong LIU
Acta Pharmaceutica Sinica B 2020;10(5):878-894
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.
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