Synthesis and Antiplasmodial Activity of New Indolone N-Oxide Derivatives

Abstract

A series of 66 new indolone-N-oxide derivatives was synthesized with three different methods. Compounds were evaluated for in vitro activity against CQ-sensitive (3D7), CQ-resistant (FcB1), and CQ and pyrimethamine cross-resistant (K1) strains of Plasmodium falciparum (P.f.), as well as for cytotoxic concentration (CC(50)) on MCF7 and KB human tumor cell lines. Compound 26 (5-methoxy-indolone-N-oxide analogue) had the most potent antiplasmodial activity in vitro (<3 nM on FcB1 and = 1.7 nM on 3D7) with a very satisfactory selectivity index (CC(50) MCF7/IC(50) FcB1: 14623; CC(50) KB/IC(50) 3D7: 198823). In in vivo experiments, compound 1 (dioxymethylene derivatives of the indolone-N-oxide) showed the best antiplasmodial activity against Plasmodium berghei, 62% inhibition of the parasitaemia at 30 mg/kg/day.

Powerful Antioxidant and Pro-Oxidant Properties ofCassia roxburghiiDC. Leaves Cultivated in Egypt in Relation to Their Anti-Infectious Activities

“…Antiplasmodial Assay Antiplasmodial activity was tested according to the protocol previously reported (18). RPMI 1640 medium [BioWhittaker, Cambrex (cat no.…”

“…The cytotoxicity was tested according to the protocol previously reported (18). Cytotoxicity was estimated on human breast cancer cells (MCF7) cultured in the same conditions as those used for P. falciparum, except that 10% human serum was replaced by 10% fetal calf serum (Cambrex).…”

Antibacterial, antifungal and antileishmanial activities of indolone-N-oxide derivatives

“…Compound 5, with an unsubstituted phenyl group (of the indolone moiety) and with a bulky naphtyl group on R 3 , was the most active INOD (MIC ¼ 3.2 mM) with low cytotoxicity against two mammalian cell lines (CC 50 /MCF7 ¼ 15.3 mM and CC 50 /KB ¼ 233 mM) 5 and against mouse peritoneal macrophages (CC 50 ¼ 12.2 mM, Table 3). Therefore, compound 5 was found to be a promising antitubercular candidate and needs further investigation against multi-drug resistant strains and other Mycobacterium strains.…”

“…5,6 In this current study, the antiprotozoal activity was extended and tested against Leishmania using two strains (L. infantum and L. amazonensis are the causative agents of visceral leishmaniasis and diffuse cutaneous leishmaniasis, respectively) ( Table 3). The antileishmanial activity was evaluated in two steps: initially, at the axenic amastigote stage and finally at the intramacrophagic amastigote stage.…”

“…This family of compounds has shown very promising antimalarial properties with low cytotoxicity. 5,6 The redox pharmacophore (nitrone function conjugated with a ketone group) is different from those of already commercialized antimicrobial agents. This pharmacophore possesses redox properties that create oxidative stress within the infected red blood cell leading to plasmodicidal activities.…”