Aminoquinoline-Pyrimidine-Based Alkyl-Piperazine Tethered Hybrids: Synthesis, Antiplasmodial Activity, and Mechanistic Studies.

Though great progress has been made to eliminate malaria globally, effective and inexpensive strategies to design new antimalarials are still required due to the problem of drug resistance to the currently used antimalarials. Herein, in continuation of our efforts to improve the therapeutic efficacy of 4-aminoquinoline-pyrimidine (4-AQ-Py) based molecular hybrids, a series of 4-AQ-Py hybrids linked through diamine-piperazine (flexible and rigid) linkers was synthesized and assessed for in vitro antiplasmodial activity. In the in vitro assay, these hybrids exhibited excellent potency and selectivity index against both the chloroquine (CQ)-sensitive (D6) and CQ-resistant (W2) strains of Plasmodium falciparum. Compound 7i was found to be the most potent (5-fold more active than CQ) against the D6 strain, while compound 7e displayed the most potency (53-fold more potent than CQ) against the W2 strain. Furthermore, nine compounds (7d, 7f-i, 7l, and 7o-q) showed better antiplasmodial activity than the reference drug artemisinin (ART) against the D6 strain, and compared to ART, seven compounds (7d-e, 7i-k, and 7p-q) demonstrated better activity against the W2 strain. All the synthesized hybrids were found noncytotoxic against the mammalian VERO cell lines. Two potent compounds, 7e and 7i, were evaluated for their in vivo antiplasmodial activity against P. berghei-infected mouse models. Additionally, one of the best active compounds, 7i, was tested for heme binding, and docking studies were conducted with Pf-DHFR to determine the primary mechanism of action of these hybrids.