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

Abstract

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 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 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 P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

Recent Advances in the Synthesis of 2-Hydroxy-1,4-naphthoquinone (Lawsone) Derivatives

“…All synthesized compounds were evaluated for their anti-infectious activities. 107 Scheme 79 Synthesis of naphthofuroquinones 256a-i and 257a-c .…”

“…In medicinal chemistry and synthetic chemistry, 2-hydroxy-1,4-naphthoquinone ( 1 ) is a highly sought-after structure due to the presence of the quinone fragment in numerous natural products with vital biological functions in plants, animals, and humans. Thus, Koumpoura et al 107 synthesized a range of non-natural molecules containing the quinone scaffold and evaluated their biological activities, including anticancer, antifungal, and antimalarial properties. The first efficient synthetic method for the production of naphthofuroquinones 256a – i was achieved through a microwave-assisted reaction between lawsone ( 1 ), various aldehydes 254a – e , and three isocyanides 255a – c , yielding derivatives in moderate-to-good yields.…”

Unprecedented linear products by a mechanochemically activated Biginelli reaction using lawsone

“…These new series of molecules exhibited interesting activities against both parasites P. falciparum and L. donovani. 29 One of the main goals in the area of organic synthesis oriented towards biologically active compounds is the research and development of environmentally safe methods in terms of efficiency, waste management and energy input, issues now addressed and termed "Green Chemistry". 30 Mechanochemistry fulls this portfolio.…”

“…These new series of molecules exhibited interesting activities against both parasites P. falciparum and L. donovani . 29…”