A class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Eleven hybrids showed better antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum in comparison to standard drug CQ. Four molecules were more potent (7-8-fold) than CQ in D6 strain, and eight molecules were found to be 5-25-fold more active against resistant strain (W2). Several compounds did not show any cytotoxicity up to a high concentration (60 μM), others exhibited mild toxicities, but the selective index for the antimalarial activity was very high for most of these hybrids. Two compounds selected for in vivo evaluation have shown excellent activity (po) in a mouse model of Plasmodium berghei without any apparent toxicity. The X-ray crystal structure of one of the compounds was also determined.

We report herein synthesis of a series of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure-activity relationship of substituted 4-aminoquinoline-based hybrids, 34 structurally diverse compounds were synthesized and tested against D6 and W2 strains of P. falciparum. Some of the compounds have shown promising antimalarial activity without toxicity against Vero cells.

Curcumin has been known to possess diverse pharmacological effects at relatively nontoxic doses; however, its therapeutic potential is severely restricted because of its low aqueous solubility and poor stability under physiological conditions. To overcome its limitations, we had previously designed several monocarbonyl curcuminoids by modifying the central β-diketone moiety of curcumin. In this study, the antibacterial activity of 33 curcuminoids from this designed library has been screened, six of which displayed potent antibacterial activity against clinically relevant Staphylococcus aureus. These curcuminoids were found to be very stable at physiological conditions and did not cause any toxicity toward mammalian cells. Mechanistically, out of these six curcuminoids, five caused instant membrane depolarization and were able to permeabilize the bacterial membrane, which could be the reason for their potent bactericidal activity and the sixth one killed staphylococcal cells without damaging the bacterial membrane. Overall, the present work established the staphylocidal potency of six water-soluble, nontoxic curcuminoids, thereby providing an impetus for the development of these lead curcuminoids for therapeutic use against S. aureus.

In recent times, the novel concept of generating hybrid molecules by pharmacophoric hybridisation approach is fast becoming an alternative to other existing strategies of drug development. These hybrids also known as 'dual drugs' or 'double drugs' are especially found to be effective in overcoming drug resistance problems. Towards this end, a lot of effort has been put for generating 4-aminoquinoline based hybrid molecules as next generation antimalarial drugs effective in malarial chemotherapy. This short review deals about the recent advances carried in the field of 4-aminoquinoline based molecular hybrids as potential antimalarial agents. It also presents a brief and simplified story on the development of 4-aminoquinolines as a mainstay in malarial research programmes.