Quinoline–Pyrimidine Hybrids: Synthesis, Antiplasmodial Activity, SAR, and Mode of Action Studies

Abstract

For the treatment of malaria which affects nearly 200 million people each year and the continued exacerbation by the emergence of drug resistance to most of the available antimalarials, the "covalent bitherapy" suggests hybrid molecules to be the next-generation antimalarial drugs. In this investigation, new hybrids of 4-aminoquinoline and pyrimidine moieties that show antiplasmodial activity in the nM range against chloroquine-resistant as well as chloroquine-sensitive strains of Plasmodium falciparum have been prepared. Cytotoxicity evaluation and mode of action of most potent hybrid molecule have been conducted.

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

“…Azoles are an important class of nitrogen containing heterocyclic compounds laced with various biological activities [25, [61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Inclusion of such heterocyclic molecules is often known to enhance the biological activities and malaria is not the exception of it.…”

“…Ten of the synthesized compounds exhibited potent activity against the CQR strain with IC 50 ≤ 660 nM. Recently, Singh et al, [66] reported the synthesis and structure-activity relationships of series of potent quinoline-pyrimidine hybrids. The in-vitro evaluation of these hybrids against CQS and CQR strains of P. falciparum depicted the activity in the nanomolar range (22.6 to 4310 nM against D10 while 43 to 7678 nM against Dd2).…”

Anti- Plasmodium falciparum activity of quinoline–sulfonamide hybrids

“…In the recent literature, several new antimalarial compounds have been described, however quinoline derivatives are still the dominate class [4][5][6][7][8][9] . A new generation of hybrids antimalarial drugs instead of combined drugs has the advantages of a lower risk of drug-drug adverse interactions and greater treatment adherence [10][11] .…”

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

“…7,8 Recent research to develop novel ACQ-based compounds that bypass CQ resistance is resulting in the synthesis of potentially promising new antimalarial agents, including 2 0 ,2 0 -dimethyldiamines, 9 ACQ heteroaryl derivatives, 10 4-aminoquinoline/clotrimazole-based hybrids, 11 aminoquinoline-pyrimidine hybrids, 12 aminoquinoline-tetrazole combinations, 13 and quinoline-pyrimidine hybrids. 14 recently reported with excellent in vitro potencies against CQR W2 and CQS 3D7 P.f. strains.…”