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).
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