Synthesis, antimalarial activity, heme binding and docking studies of N -substituted 4-aminoquinoline-pyrimidine molecular hybrids

Docking of New Designed Compounds Derived from 1,6-Dihydro-1,3,5-triazine-2,4-diamine Toward Quadruple Mutant Plasmodium Dihydrofolate Reductase

“…Various strategies have been implemented to discover new antimalarial drugs [6]. Some researchers try to find a new antimalarial drug base on the molecular docking study [7][8][9][10][11][12]. Binding free energy between ligand-receptor of the best pose (conformation) resulted from docking procedure are then calculated via Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) approach [13][14].…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…Replacement of chloro at pyrimidine by nitrogen‐containing heterocycles ( 118 and 199 ) could increase the activity against CQR Dd2 strain to some extent, but aminoalkanols reduced the activity . Similar SARs were also observed for quinoline‐pyrimidine hybrids 120 to 122 (IC 50 : 120‐440, 140‐240, and 5‐30 nM against CQS 3D7 strain, respectively; 500‐700, 580‐1,170, and 16‐210 nM against CQR Dd2 strain, respectively), quinoline‐pyrimidine hybrids 123 to 130 ( 123 and 124 attaching furan skeleton, IC 50 : 38‐61 and 39‐257 nM against CQS 3D7 and CQR Dd2 strains, respectively; 125 and 126 with piperonyl fragment, IC 50 : 20‐150 and 50‐990 nM against CQS 3D7 and CQR Dd2 strains, respectively; 127 and 128 with pyridine motif, IC 50 : 30‐1193 and 39‐1143 nM against CQS 3D7 and CQR Dd2 strains, respectively; 129 and 130 with thiophene motif, IC 50 : 32.8‐83.7 and 18.9‐409.1 nM against CQS 3D7 and CQR Dd2 strains, respectively) bearing an aromatic ring at the amino near to pyrimidine moiety, and quinoline‐pyrimidine hybrids 131 (IC 50 : 32‐204 and 32‐1018 nM against CQS 3D7 and CQR Dd2 strains, respectively), 132 (IC 50 : 19‐6022 and 46‐9994 nM against CQS 3D7 and CQR Dd2 strains, respectively) incorporating modified anilines at the pyrimidine end. Furthermore, for hybrids 122 , the relative contribution order of nitrogen‐containing heterocycles at pyrimidine moiety was 4‐ethyl piperazine > 4‐methyl piperazine > morpholine > piperidine.…”

Quinoline-Based Hybrid Compounds with Antimalarial Activity

“…Maurya et al prepared 4-aminoquinoline-pyrimidine hybrid compounds that obeyed Lipinski’s rule of five. Those that obeyed the rule also exhibited good antimalarial activity [ 2 ]. The compounds exhibited potent antimalarial activity against strains of P. falciparum (D6 and W2) with IC 50 values 0.038–0.044 μM which was equipotent to artemisinin, a potent antimalarial drug with IC 50 = 0.045 μM [ 2 ].…”

“…Those that obeyed the rule also exhibited good antimalarial activity [ 2 ]. The compounds exhibited potent antimalarial activity against strains of P. falciparum (D6 and W2) with IC 50 values 0.038–0.044 μM which was equipotent to artemisinin, a potent antimalarial drug with IC 50 = 0.045 μM [ 2 ]. Salahuddin et al prepared 4-aminochloroquinoline-sulfonamides hybrid compounds and the most potent compounds against P. falciparum had log P values nearly equal to quinine and chloroquine [ 74 ].…”

“…Pregnant women and young children in the sub-tropical regions are more prone to malaria infection. In 2015, 214 million infections were reported, with approximately 438,000 deaths and the African region accounted for 90% of the deaths [ 1 , 2 , 3 ]. Malaria is caused by five parasites of the genus Plasmodium , but the majority of deaths are caused by Plasmodium falciparum and Plasmodium vivax [ 1 , 4 , 5 , 6 ].…”