Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents

Abstract

Background: Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively.

Results: The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a-g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one fungus i.e. Aspergillus niger [corrected]. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs.

Conclusions: In vitro antiplasmodial IC₅₀ value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

Keywords: Antifungal; Antimalarial; Antimicrobial; Conformational studies; DHP; Falcipain-2; Plasmodium falciparum; Pyrazole.

Fig. 1

Drug designing by molecular hybridisation approach for the synthesis of new molecular hybrids

Scheme 1

Synthesis of diethyl 4-(4-(((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene aminocarbamoyl)methoxy)phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (5a–g)

Fig. 2

Four possible isomeric form for 5a

Fig. 3

Assignment of various characteristic peaks and 2D correlation of 5a

Fig. 4

Comparison of δ of two isomers of 5a in CDCl₃ and DMSO

Fig. 5

Graphical representation of % inhibition of compounds 5a–5g

Fig. 6

Bilogical assay for antibacterial activity. Activity against bacteria (B. cereus), activity against fungi (A. niger)

Fig. 7

The interaction of ligand E64 into the binding sites of FP-2(PDB ID: 3BPF)

Fig. 8

Interactions of the 5d into the binding sites of FP-2(PDB ID: 3BPF)