Primaquine derivatives: Modifications of the terminal amino group

Abstract

a b s t r a c tNumerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain antimalarial agents with improved bioavailability, reduced toxicity and/or prolonged activity. Modifications of the terminal amino group were made with the main idea to prevent the metabolic pathway leading to inactive and toxic carboxyprimaquine (follow-on strategy), but also to get compounds with different activity (repurposing strategy). The modifications undertaken until 2009 were included in a review published in the same year. The present review covers various classes of primaquine N-derivatives with diverse biological profiles, prepared in the last decade by our research group as well as the others. We have summarized the synthetic procedures applied for their preparation and discussed the main biological results. Several hits for the development of novel antiplasmodial, anticancer, antimycobacterial and antibiofilm agents were identified.

Tafenoquine: A Step toward Malaria Elimination

“…99 Given the intimate link between 8-aminoquinolines' metabolism and their activities/toxicities, numerous primaquine derivatives have been synthesized through modification of the quinoline core and the terminal amino group to improve the therapeutic window. 100,101 Many primaquine derivatives showed reduced cytotoxicity in cell cultures in addition to higher potency against the P. falciparum blood stage and P. berghei liver stage in vitro. 101 However, few studies have compared the efficacies of these derivatives in multiple Plasmodium life stages, and even fewer have assessed their radical curative activities and the hemolytic toxicity in the context of G6PD deficiency.…”

“…100,101 Many primaquine derivatives showed reduced cytotoxicity in cell cultures in addition to higher potency against the P. falciparum blood stage and P. berghei liver stage in vitro. 101 However, few studies have compared the efficacies of these derivatives in multiple Plasmodium life stages, and even fewer have assessed their radical curative activities and the hemolytic toxicity in the context of G6PD deficiency. As one example, a cohort of primaquine-thiazolidinones were generated and shown to suppress rodent and avian malaria transmission (Figure 1).…”

Anthranilamides with quinoline and β-carboline scaffolds: design, synthesis, and biological activity

“…To design compounds with improved activity, we combined anthranilic acid motif with other two scaffolds known for their antiproliferative properties, namely quinoline and β-carboline. Considering the numerous preclinical and clinical trials confirming the usefulness of antimalarial drugs in cancer therapy [ 10 – 16 ] and based on our previous experience with primaquine (PQ) and chloroquine derivatives with pronounced antiproliferative activities [ 17 , 18 ], we have chosen N 1 -(7-chloroquinolin-4-yl)butane-1,4-diamine (CQ), as a simplified chloroquine molecule, and PQ-base as amino components for the preparation of anthranilamides. On the other hand, β-carboline alkaloids (harmane, harmine, and harmaline) possess diverse biological activities, including antimalarial and antiproliferative activity [ 19 – 37 ].…”

Chloroquine fumardiamides as novel quorum sensing inhibitors

“…8 Our studies have focused on the derivatization of the quinoline drug primaquine (PQ) with the aim to get novel biologically active agents. 9 A literature survey revealed a number of reports on quinoline derivatives as effective antagonists of PqsR, the receptor of pqs system of the human pathogen Pseudomonas aeruginosa, which controls the expression of various virulence factors and is involved in the biofilm formation. Based on the scaffold of the quinolone signal molecule PQS (2-heptyl-3-hydroxy-4(1H)-quinolone) and its precursor HHQ (2-heptyl-4-hydroxyquinoline), several classes of quinoline and quinazolinone PqsR antagonists were developed.…”

“…1), whereas the most susceptible microorganisms were Enterococcus faecalis and S. aureus, followed by E. coli, Streptococcus pneumoniae and P. aeruginosa. Our compound library was further enriched with analogous derivatives bearing mefloquine (MQ) (7)(8)(9)(10)(11)(12) or chloroquine (CQ) pharmacophores (13-18) (Fig. 1).…”