We have recently discovered a family of 2,6-diaminopurine derivatives acting as DENV inhibitors by targeting an allosteric pocket on the thumb of the viral NS5 polymerase. Although the following target-based optimization allowed conversion of the hits into broad-spectrum DENV/ZIKV inhibitors, no improvement of the antiviral potency was reached. Herein, we applied a phenotypic scaffold-morphing approach to explore additional biologically relevant chemical space around the original hits by converting the flat purine derivatives into more complex chemotypes characterized by a higher degree of saturation. A new microwave-assisted one-pot three-step protocol was also developed to quickly generate chemotypes 6 and 7. Cell-based phenotypic screening allowed identification of promising antiflaviviral agents belonging to different chemotypes. Compound 9d emerged as the most promising broad-spectrum antiviral, being 6 times more potent than ribavirin (RBV) against DENV and 3 times more potent than 7-deaza-2′-C-methyladenosine (7DMA) against ZIKV with good selectivity indexes (>46 and >41, respectively).

Scaffold Morphing Approach To Expand the Toolbox of Broad-Spectrum Antivirals Blocking Dengue/Zika Replication / Vincetti, Paolo; Kaptein, Suzanne J. F.; Costantino, Gabriele; Neyts, Johan; Radi, Marco. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 558-563. [10.1021/acsmedchemlett.8b00583]

Scaffold Morphing Approach To Expand the Toolbox of Broad-Spectrum Antivirals Blocking Dengue/Zika Replication

Paolo Vincetti;Gabriele Costantino;Marco Radi
2019

Abstract

We have recently discovered a family of 2,6-diaminopurine derivatives acting as DENV inhibitors by targeting an allosteric pocket on the thumb of the viral NS5 polymerase. Although the following target-based optimization allowed conversion of the hits into broad-spectrum DENV/ZIKV inhibitors, no improvement of the antiviral potency was reached. Herein, we applied a phenotypic scaffold-morphing approach to explore additional biologically relevant chemical space around the original hits by converting the flat purine derivatives into more complex chemotypes characterized by a higher degree of saturation. A new microwave-assisted one-pot three-step protocol was also developed to quickly generate chemotypes 6 and 7. Cell-based phenotypic screening allowed identification of promising antiflaviviral agents belonging to different chemotypes. Compound 9d emerged as the most promising broad-spectrum antiviral, being 6 times more potent than ribavirin (RBV) against DENV and 3 times more potent than 7-deaza-2′-C-methyladenosine (7DMA) against ZIKV with good selectivity indexes (>46 and >41, respectively).
Scaffold Morphing Approach To Expand the Toolbox of Broad-Spectrum Antivirals Blocking Dengue/Zika Replication / Vincetti, Paolo; Kaptein, Suzanne J. F.; Costantino, Gabriele; Neyts, Johan; Radi, Marco. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 558-563. [10.1021/acsmedchemlett.8b00583]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2857840
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