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Molecules 2017, 22(12), 2102; doi:10.3390/molecules22122102

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

1
Department of Biomedical, Surgical and Dental Sciences (DiSBIOC), University of Milan, Via Pascal 36, 20133 Milan, Italy
2
Department of Pharmacological & Biomolecular Sciences (DiSFeB), University of Milan, Via Pascal 36, 20133 Milan, Italy
3
Department of Pharmaceuticals Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
4
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (LSHTM), Keppel Street, London WC1E 7HT, UK
5
School of Pharmacy, University of Camerino, Via d’Accorso 16, 63032 Camerino, MC, Italy
6
Singapore Immunology Network (SIgN), Agency for Science Technology and Research, Biopolis, Singapore 138648, Singapore
7
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand
8
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research building, University of Oxford Old Road Campus, Oxford OX3 7FZ, UK
9
Aphad Srl, Via della Resistenza 65, 20090 Buccinasco, Milan, Italy
10
NeED Pharmaceuticals Srl, Viale Ortles 22/4, 20139 Milan, Italy
These authors contributed equally to the work.
Current address: Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
§
Current address: Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
*
Author to whom correspondence should be addressed.
Received: 24 October 2017 / Revised: 20 November 2017 / Accepted: 29 November 2017 / Published: 1 December 2017
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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. View Full-Text
Keywords: malaria; 4-aminoquinoline; drug resistance; P. falciparum; P. vivax malaria; 4-aminoquinoline; drug resistance; P. falciparum; P. vivax
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MDPI and ACS Style

Basilico, N.; Parapini, S.; Sparatore, A.; Romeo, S.; Misiano, P.; Vivas, L.; Yardley, V.; Croft, S.L.; Habluetzel, A.; Lucantoni, L.; Renia, L.; Russell, B.; Suwanarusk, R.; Nosten, F.; Dondio, G.; Bigogno, C.; Jabes, D.; Taramelli, D. 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. Molecules 2017, 22, 2102.

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