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. 2016 Oct 13;59(19):9262-9268.
doi: 10.1021/acs.jmedchem.6b00461. Epub 2016 Sep 22.

Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1

Yu Zhao  1 , Qiong Gu  1   2 , Susan L Morris-Natschke  1 , Chin-Ho Chen  3 , Kuo-Hsiung Lee  1   4
Affiliations

Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1

Yu Zhao et al. J Med Chem. .

Abstract

Two "privileged fragments", caffeic acid and piperazine, were integrated into bevirimat producing new derivatives with improved activity against HIV-1/NL4-3 and NL4-3/V370A carrying the most prevalent bevirimat-resistant polymorphism. The activity of one of these, 18c, was increased by 3-fold against NL4-3 and 51-fold against NL4-3/V370A. Moreover, 18c is a maturation inhibitor with improved metabolic stability. Our study suggested that integration of privileged motifs into promising natural product skeletons is an effective strategy for discovering potent derivatives.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of betulinic acid (1), bevirimat (2), and its analogues with improved anti-HIV activity against wild-type virus (3) or BVM-R virus (4).
Figure 2
Figure 2
Caffeic acid related compounds exhibit potent anti-HIV activity as a single molecule or as a substructure.
Figure 3
Figure 3
Incorporation of two privileged fragments into the structure of 2 to design new derivatives.
Figure 4
Figure 4
Joining appropriate privileged structures to the triterpene skeleton can generate significant potency.
Figure 5
Figure 5
(A) Compound 18c did not inhibit HIV-1 Env-mediated cell–cell fusion. Each data point in the figure represents the average of two independent tests. (B) Compound 18c showed no activity in NL4-3 infection of TZM-bl assays. NL4-3 infection of TZM-bl cells without compounds was used as control. % control infection is 100 × RLUcpd/RLUctr. RLUcpd and RLUctr are the relative luminescence units of the experimental infection and control infection, respectively. All compounds were tested at 2 µM. The numbers in the figure are derived from the average of two tests.
Scheme 1
Scheme 1. Synthesis of Compounds 14c, 18a– c, 19, and 20a
a(a) 1-Boc-piperazine, HOBt, EDCI, Et3N, DCM, overnight; (b) 13a,c TFA, DCM, 2 h; or 13b ZnBr2, DCM, 24 h; (c) oxalyl chloride, DCM, then deprotected 13a–c (for 16a–c) or 1-Boc-piperazine (for 20), Et3N, DCM, 6 h; (d) 4 N NaOH, THF/MeOH, overnight; (e) 2,2-dimethylsuccinic anhydride, DMAP, pyridine, microwave 155 °C, 2 h; (f) 4 N HCl in EtOAc, DCM, 4 h.
Scheme 2
Scheme 2. Synthesis of Compound 23a
a(a) (i) 13c, TFA, CH2Cl2 2 h; (ii) HOBt, EDCI, Et3N, overnight.; (b) 2,2-dimethylsuccinic anhydride, DMAP, pyridine, microwave 155 °C, 2 h.
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