Design, Synthesis and Antimalarial Activity of Some New 2-Hydroxy-1,4-naphthoquinone-4-hydroxyaniline Hybrid Mannich Bases

Abstract

In this study, some novel 2-hydroxy-1,4-naphthoquinone-4-hydroxyaniline hybrid Mannich bases were designed, synthesized and evaluated for in vitro antimalarial activity. The design strategy of novel hybrid molecules involves fusion between the pharmacophoric moieties of lawsone (2-hydroxy-1,4-naphthoquinone, a residue from atovaquone) and Mannich substituted 4-hydroxyaniline (4-aminophenol, a residue from amodiaquine) on the basis of molecular hybridization strategy. Newly designed compounds, 5a-f were also studied for drug-likeness assessment based on Lipinski’s rule of five. All the synthesized compounds exhibited some degree of in vitro antimalarial activity against the chloroquine-sensitive strain (RKL-2) of P. falciparum at the tested dose (1 mg/mL), which was considerably less than that of the standard drug, chloroquine (0.1 mg/mL). However, compounds with propyl, 5a (IC₅₀ 0.453 μg/mL) and morpholinyl, 5f (IC₅₀ 0.391 μg/mL) substitutions showed comparatively better activity than rest of the synthesized analogues. Compound 5f (IC₅₀ 0.993 μg/mL) was found to possess higher antimalarial effectiveness than compound 5a (IC₅₀ 2.92 μg/mL) against resistant strain (RKL-9) of P. falciparum. The activity of these compounds against the resistant strain was also less than that of chloroquine (IC₅₀ 0.299 μg/mL). From results, it is clear that compounds having substitutions like smaller alkyl groups (n-propyl, 5a; isopropyl, 5b) or saturated heterocyclic moiety (morpholinyl, 5f) possess superior antimalarial activity in comparison to other compounds substituted with bulky alkyl (diisopropyl, 5c; n-butyl, 5d) or aryl (phenyl, 5e) moieties. Further, since all the compounds exhibited favourable drug-like properties a reasonable correlation therefore appears to exist between their drug-likeness and antimalarial activities.