Synthesis, SAR, and Docking Studies Disclose 2-Arylfuran-1,4-naphthoquinones as In Vitro Antiplasmodial Hits

Abstract

A total of 28 lapachol-related naphthoquinones with four different scaffolds were synthesized and spectroscopically characterized. In vitro antiplasmodial activity was assayed against the chloroquine-resistant Plasmodium falciparum W2 strain by the parasite lactate dehydrogenase (pLDH) method. Cytotoxicity against Hep G2A16 cell was determined by the MTT assay. All compounds disclosed higher in vitro antiplasmodial activity than lapachol. Ortho- and para-naphthoquinones with a furan ring fused to the quinonoid moiety were more potent than 2-hydroxy-3-(1′-alkenyl)-1,4-naphthoquinones, while ortho-furanonaphthoquinones were more cytotoxic. Molecular docking to Plasmodium targets Pfcyt bc1 complex and PfDHOD enzyme showed that five out of the 28 naphthoquinones disclosed favorable binding energies. Furanonaphthoquinones endowed with an aryl moiety linked to the furan ring are highlighted as new in vitro antiplasmodial lead compounds and warrant further investigation.

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

“…Finally, concerning these series of naphthofuroquinones, it is worth pointing out that many of our compounds are 2-to 5-fold more active against P. falciparum than derivative 6 reported by Borgati et al 12 Among the other evaluated compounds, while lawsone and iodolawsone are weak to very weak inhibitors of P. falciparum in vitro, compounds 28 and 29 seem more interesting. For both couples of compounds bearing either a N-tert-butyl or N-butyl group, the IC 50 values are 1.4 and 1.9 μM, respectively, associated with a weak cytotoxicity (CC 50 > 50 μM) resulting in promising SIs (>36 and >26, respectively).…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 8.15 (dd, J = 7.6, 1.0 Hz, 1H), 8.02 (dd, J = 7.6, 1.0 Hz, 1H), 7.67 (td, J = 7.5, 1.3 Hz, 1H), 7.59 (td, J = 7.5, 1.3 Hz, 1H), 6.72 (s, 2H), 4.98 (s, 1H), 3.90 (s, 3H), 3.89 (s, 6H), 1.50 (s, 9H). 13 (12). The compound was synthesized by following the above-mentioned general procedure (0.…”

“…Unfortunately, strong P. falciparum resistance against atovaquone arises rapidly in the field. In this respect, efforts to design and prepare naphthoquinones and naphthofuroquinones based on lawsone scaffold have been pursued worldwide: 26 Borgati et al 12 reported the synthesis of a series of naphthoquinones and naphthofuroquinones through functionalization of lawsone either on the 2-hydroxy group affording alkoxy derivatives or on the C-3 alkene carbon atom, followed by cyclization, thus leading to naphthofuroquinones. Among all the synthesized compounds, naphthofuroquinone 6 exhibited the lowest IC 50 value against the chloroquine-resistant P. falciparum W2 strain (Figure 2).…”

“…Among various classes of quinones, naphthoquinones and especially naphthofuroquinones have attracted increasing interest for their pharmacological activities. Naphthofuroquinone derivatives can be obtained from natural sources , but also via synthetic approaches, giving rise to compounds with various structures and biological properties, for example, cytotoxicity against tumor cells, inhibition of tyrosine kinases receptors, and antimalarial or antidiabetic activity (Figure ).…”

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

“…In 2017, Borgati et al [ 83 ] reported a series of four families of compounds issued from structural modifications of the lawsone compound and their in vitro antiplasmodial activities against the chloroquine-resistant P. falciparum W2 strain. The general retrosynthetic scheme of their work is presented below ( Scheme 8 ).…”