Bioinspired Pyrano[2,3-f]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation

Author:

Khalymbadzha Igor A.1,Fatykhov Ramil F.1,Butorin Ilya I.1ORCID,Sharapov Ainur D.1ORCID,Potapova Anastasia P.1,Muthipeedika Nibin Joy1,Zyryanov Grigory V.1,Melekhin Vsevolod V.12ORCID,Tokhtueva Maria D.1ORCID,Deev Sergey L.1,Kukhanova Marina K.3,Mochulskaya Nataliya N.1,Tsurkan Mikhail V.4ORCID

Affiliation:

1. Department of Organic and Biomolecular Chemistry, Ural Federal University, 620002 Yekaterinburg, Russia

2. Department of Medical Biology and Genetics, Ural State Medical University, 620028 Yekaterinburg, Russia

3. Engelhardt Institute of Molecular Biology, 119991 Moscow, Russia

4. Leibniz Institute of Polymer Research Dresden, 01069 Dresden, Germany

Abstract

We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established.

Funder

Russian Science Foundation

Publisher

MDPI AG

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