Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains |
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| 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 |
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| 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) |
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| 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‐pyrido1,2‐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. |
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| Keywords: | antiprotozoal agents chloroquine cytisine derivatives medicinal chemistry quinolizidine derivatives |
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