In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial

Abstract

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16–53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P. berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.

Quinolizidine-Based Variations and Antifungal Activity of Eight Lupinus Species Grown under Greenhouse Conditions

“…The identified QAs have already been reported as phytocomponents in Lupinus species. Some of them are commonly found as the most abundant QAs, being part of certain mixtures at differentiated proportions between species or even due to the effects caused by biotic and abiotic factors [ 13 , 44 ]. Qualitative and quantitative comparisons were made between the eight lupin species propagated under the same conditions in the present study.…”

Quinolines and Quinolones as Antibacterial, Antifungal, Anti-virulence, Antiviral and Anti-parasitic Agents

“…Hybrid derivative 100 and 101 ( Fig. 14), contained 4-aminoquinoline and a quinolizidine (Sparatore et al 2005) fragments displayed a very attractive bioactivity profile (Basilico et al 2017). Both racemic (1R/1S)-AM1 and enantiomers exhibited an antimalarial activity in low nanomolar range against sensitive and CQ resistant strains, as well as against MDR strain of P. falciparum.…”

Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme

“…The reported in vivo therapeutic efficacy of chloroquine seems to be better than those of 3a and 12a. 32 However, 3a and 12a would be superior to chloroquine against chloroquine-resistant strains (the P. berghei strain is chloroquine-sensitive).…”