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. 2020 May;10(5):878-894.
doi: 10.1016/j.apsb.2019.08.013. Epub 2019 Sep 14.

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

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
Affiliations

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

Dongwei Kang et al. Acta Pharm Sin B. 2020 May.

Abstract

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-5a2. 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 (L100I, K103N, Y181C, Y188L and E138K) 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.

Keywords: HIV-1; Hydrophobic channel; NNIBP; NNRTIs; Thiophene[3,2-d]pyrimidine.

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Figures

Image 1
Graphical abstract
Fig. 1
Figure 1
Chemical structures of second-generation NNRTI drugs and thiophene[3,2-d]pyrimidine lead K-5a2 and 25a.
Fig. 2
Figure 2
Design of the novel thiophene[3,2-d]pyrimidine derivatives.
Scheme 1
Scheme 1
Synthesis of 6a–k. Reagents and conditions: (i) Pd(PPh3)4, K2CO3, DMF, H2O, 100 °C.
Scheme 2
Scheme 2
Synthesis of the target compounds 11–32. Reagents and conditions: (i) 6a–k, DMF, K2CO3, r.t.; (ii) BINAP, PdCl2(PPh3)2, Cs2CO3, N-(tert-butoxycarbonyl)-4-aminopiperidine, 1,4-dioxane, 120 °C; (iii) TFA, DCM, r.t.; (iv) 4-(bromomethyl) benzenesulfonamide or 4-(chloromethyl) benzamide, DMF, K2CO3, r.t.
Fig. 3
Figure 3
Regression analysis of pIC50 and pEC50 values for the newly synthesized derivatives.
Fig. 4
Figure 4
Final geometries for 26 in complexs with WT (A), K103N (B) and RES056 (C) RT. Hydrogen-bonding interactions for the –NH guanidine group and the protonated nitrogen atom with K101 and K103 of the protein as well as the π-stacking with F227 and Y188 are also highlighted.
Fig. 5
Figure 5
The plasma concentration–time profiles of 26 in Wistar rat following p.o. administration (20 mg/kg) and i.v. administration (2 mg/kg).
Fig. 6
Figure 6
The relative body weight changes of Kunming mice in different groups (26 and blank).
See this image and copyright information in PMC

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