Novel 4-Aminoquinolines Active against Chloroquine-Resistant and Sensitive P. falciparum Strains that also Inhibit Botulinum Serotype A

Abstract

We report on the initial result of the coupling of 4-amino-7-chloroquinoline with steroidal and adamantane constituents to provide small molecules with excellent in vitro antimalarial activities (IC90 (W2) down to 6.74 nM). The same entities also inhibit the botulinum neurotoxin serotype A light chain metalloprotease at low micromolar levels (7-31 microM). Interestingly, structural features imparting increased antimalarial activity also provide increased metalloprotease inhibition, thus allowing for simultaneous compound optimizations against distinct targets.

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

“…Recently, Idenovi et al [106] reported a new class of hybrid molecule (CQ-Cholic acid derivatives, 41a and b, Figure 31) which was originally intended to develop as Botulinum neurotoxin inhibitors [106][107][108], but further study indicated that they are better inhibitors of malarial parasite too [106]. The hybrid compounds showed better activity profile on some strains than the standard drugs CQ, artemisnin and MFQ.…”

Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker

“…Indeed, the binding of both active entities allows to increase the bioavailability of the final dual molecule and to merge active molecules with independent modes of action to prevent the emergence of resistance. 25 This dual prodrug strategy has been applied to malaria 20,[26][27][28][29][30][31][32][33][34] and to various other diseases such as tuberculosis, 35 cancer, 36 and HIV. [37][38][39] In particular, combination of two active components targeting the heme detoxification pathway and the thiol network of malaria parasites was shown to provide the proof of concept both in vitro and in vivo, and at the molecular level.…”

Recent developments in the design and synthesis of hybrid molecules basedon aminoquinoline ring and their antiplasmodial evaluation

“…The success of this hybridization approach, having a wonderful example of trioxaquines [110] or artemisinin-quinine hybrid [183], stimulates further organic, medicinal and biochemical activities to struggle malaria, the world's most widespread and devastating infectious disease. The hybridization approach will represent more and more a new challenge for medicinal chemists, pharmacologists and biochemists [184][185][186][187][188][189][190] because it benefits not only to drug-design efforts, but also to better understand drug resistant parasites' problem.…”