Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides.

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for and 2D-NMR spectra of confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against , , and . Among the naphthofuroquinone series, exhibited comparatively the best activity against (IC = 2.5 μM) and (MIC = 9 μM) with better () or equivalent () values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, exhibited a moderate activity against with a good selectivity index (SI > 36) while also a very high potency against (IC = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for , Pfbc1, and PfDHODH, where showed the most favorable interactions.