Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines)

Abstract

In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (P. falciparum), antileishmanial (L. donovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, β-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (41, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (P. berghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2 -1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.

Novel Potent Metallocenes against Liver Stage Malaria

“…In primacenes, quinoline's C-5 is not substituted, so hemotoxic 5-hydroxylated metabolites can arise; however, such problem would be minimized if the oral bioavailability of the primacenes is confirmed to be significantly higher than that of PQ or TFQ. These aspects remain to be evaluated for primacenes, but it is interesting that novel bis(8-aminoquinolines) derived from PQ, bearing an unsubstituted quinoline C-5, have a negligible propensity to induce the formation of methemoglobin, together with an improved antimalarial activity over that of PQ (17).…”

“Recycling” Classical Drugs for Malaria

“…70 The same authors also reported bis(8-aminoquinolines) 44 ( Figure 17) with promising antimalarial activity in vitro against drug-sensitive (D6, IC 50 = 1.6−4.76 μg/mL) and drug-resistant (W2, IC 50 = 0.3−3.6 μg/mL) strains of P. falciparum, and potent in vivo activity in the rodent model of malarial infection. 71 The compounds had also decreased hematotoxicity, as compared to PQ, and moderately inhibited β-hematin formation, suggesting this as a plausible pathway of their antimalarial activity. 71 Following these discoveries, the same group reported the design, synthesis, and evaluation of three new series of PQ-based 8-AQ modified at the terminal primary amine (45, Figure 17).…”

“…71 The compounds had also decreased hematotoxicity, as compared to PQ, and moderately inhibited β-hematin formation, suggesting this as a plausible pathway of their antimalarial activity. 71 Following these discoveries, the same group reported the design, synthesis, and evaluation of three new series of PQ-based 8-AQ modified at the terminal primary amine (45, Figure 17). 72 The presence of carboxyl groups seemed disadvantageous, as compounds from series 1 (IC 50 = 4.76 and 4.2 μg/mL) were less potent than PQ (IC 50 = 2.8 and 2.0 μg/mL) against P. falciparum W2 and D6 strains, respectively.…”

Synthesis of 2-[(quinolin-8-yloxy)methyl]quinoline-3-carboxylic acid derivatives

“…Some well-known bisquinoline drugs such as piperaquine, hydroxypiperaquine [5][6][7], WR 268,668 B [8], and N,N′-bis (-7-chloroquinolin-4-yl) alkanediamine [9] are active against chloroquine resistant strains of malaria. Some new bisquinoline derivatives also possess interesting in vitro antileishmanial [10], antitumor [11], antiprotozoal and antimicrobial activities [12] by forming a complex with the DNA double helix. Palit et al [10] has reported that 1,1-bis-[(5-chloro-8-quinolyl) oxy]methane (1, Figure 1) exhibits the most significant antileishmanial activity.…”