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Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains
Authors:Dr. Bruno Tasso  Dr. Federica Novelli  Dr. Michele Tonelli  Dr. Anna Barteselli  Dr. Nicoletta Basilico  Dr. Silvia Parapini  Prof. Donatella Taramelli  Prof. Anna Sparatore  Prof. Fabio Sparatore
Affiliation:1. Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16131 Genova (Italy);2. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano via Mangiagalli 25, 20133 Milano (Italy);3. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano via C. Pascal 36, 20133 Milano (Italy);4. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano via C. Pascal, 36, 20133 Milano (Italy)
Abstract:Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria‐related deaths, has developed resistance against this drug. Twenty‐seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro‐2H‐quinolizine and 1,2,3,4,5,6‐hexahydro‐1,5‐methano‐8H‐pyrido[1,2‐a][1,5]diazocin‐8‐one, were synthesized and tested for activity against D‐10 (CQ‐susceptible) and W‐2 (CQ‐resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub‐micromolar IC50 values. Eleven compounds were found to be 2.7‐ to 13.4‐fold more potent than CQ against the W‐2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC‐1 and HepG2) along with easier synthetic accessibility. Replacement of the 4‐NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria.
Keywords:antiprotozoal agents  chloroquine  cytisine derivatives  medicinal chemistry  quinolizidine derivatives
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