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. 2021 Oct 26;11(11):1584.
doi: 10.3390/biom11111584.

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Rosarita D'Orsi  1 , Maria Funicello  1 , Teresa Laurita  1 , Paolo Lupattelli  1 , Federico Berti  2 , Lucia Chiummiento  1
Affiliations

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Rosarita D'Orsi et al. Biomolecules. .

Abstract

Here, we report the synthesis, enzyme inhibition and structure-activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P' and P'' and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/ml BSA. Compounds 9a-c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.

Keywords: HIV-protease inhibitors; biological screening; heteroaryl carboxyamides; modeling; pseudo-symmetric core; synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Commercial and not HIV-protease inhibitors.
Figure 2
Figure 2
Examples of pseudo-symmetrical core of HIV-protease inhibitors.
Scheme 1
Scheme 1
Synthesis of inhibitors 7a–c, 8a–c and 9a–c: (a) BnNH2, i-PrOH, 60°C, 4h (88% yield); (b) arylsulfonyl chloride, Et3N, CH2Cl2, rt, 24h (5a 94%; 5b 85%; 5c 90%); (c) TFA/CH2Cl2 30%, rt, 1 h; then Et3N; (d) 5-heteroarylcarboxylic acid, EDC, HOBt, then 6a–c, iPr2NEt, CH2Cl2, 24h, rt (7a, 50%; 7b 57%; 7c 55%; 8a 53%; 8b 54%; 8c 56%; 9a 33%; 9b 43%; 9c 44%).
Scheme 2
Scheme 2
(a) BnNH2, i-PrOH, 60 °C, 4 h; (b) p-TsOH, MeCN, 5 h, rt (60% yield from 3); (c) 5-heteroarylcarboxylic acid, EDC, HOBt, then 10, iPr2NEt, CH2Cl2, 24 h, rt; (d) p-methoxybenzene sulfonyl chloride, Et3N, CH2Cl2.
Figure 3
Figure 3
(a): Overlay of the crystallographic structure of the Hiv-pr complex with darunavir and the model structure of the complex of 9b; (b): overlay of the model structures of the complexes of 7b, 8b and 9b with the protease; (c): interactions of the dioxabicyclo octane group of darunavir with the protein; (d): interactions of the indole system of 9b with the protein.
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