Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives

Abstract

Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug-drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC₅₀ = 0.0130 ± 0.0002 μM) and the K1 strain (EC₅₀ = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

Keywords: 4-aminoquinoline; antimalarial; docking; hybrid; pyrano[2,3-c]pyrazole.

Figure 1

Miscellaneous molecular hybrid based on 4-aminoquinolines, primaquine, and mefloquine (I–VIII) reported from 2005–2019.

Figure 2

The component of hybrid compounds comprised of chloroquine motif (in blue) and pyrano[2,3-c]pyrazole moiety (in pink).

Figure 3

Proposed nucleophilic attack of pyrano[2,3-c]pyrazole derivatives to the 4-aminoquinoline scaffold to obtain the molecular hybrids (4a–e).

Figure 4

Natural population analysis distribution for the optimized 1d structure with the atoms labeled.

Figure 5

(a) Position of the enzyme active site and cofactor binding site of PfLDH. Both the pink and green space-filling calotte models represent the binding position of the co-crystallized inhibitors, 3,5-dihydroxy-2-naphthoic acid and chloroquine. (b) Superposition of the docked ligand with the co-crystallized ligand (blue carbon atoms) (RMSD value of 1.32 Å). Best binding pose of compound 4b in the first (c) and second (e) cluster results. (c) 2D-docking pose of compound 4b in the first (d) and second (f) cluster results.

Figure 6

The structure-activity relationship of synthesized compounds, 4a–e.

Figure 7

Reagents and conditions: (i) EtOH, reflux 1–2 h, R = benzaldehyde, 4-ethylbenzaldehyde, isobutyraldehyde, 4-hydroxybenzaldehyde and furaldehyde; (ii) reflux 1h; (iii) reflux 3 h and (iv) DMSO, r.t.