In vitro and in silico evaluation of fluorinated diphenylamine chalcone derivatives as potential antimalarial and anticancer agents

Abstract

A series of novel diphenylamine fluorinated chalcone derivatives (B1-B10) were synthesized and characterized using ¹H and ¹³C NMR, IR, and MS, and purity was determined using HPLC. The compounds were evaluated for their antimicrobial, antimalarial, and anticancer activities, with Chloramphenicol, Griseofulvin, and 5-Fluorouracil serving as standard reference drugs. Notably, B6 exhibited excellent antifungal activity, comparable to that of the standard drug Griseofulvin. Compounds B3 and B5 showed strong antimalarial effects against Plasmodium falciparum. Both B3 and B5 exhibit substantial cytotoxicity against HeLa cells, with IC₅₀ values of 24.53 µg/ml for B5 and 32.42 µg/ml for B3. These results clearly demonstrate that both compounds outperform the standard drug 5-Fluorouracil, establishing their strong potential as effective alternatives in cancer therapy. Molecular docking studies revealed that B3 and B6 effectively interacted with the active site of Falcilysin, while B5 and B7 showed favourable binding to proteins 6GUE and 2 × 7 F. Molecular dynamics simulations confirmed the stability of B3 and B6 with P. falciparum, while B5 and B3 exhibited promising interactions with 6GUE and 2X7F. These results suggest that compounds B3 and B5 are potential lead candidates for developing novel antimicrobial, antimalarial, and anticancer therapies.

Keywords: Fluorinated diphenylamine Chalcones; In Silico study; In vitro biological evaluation; Methoxy functional group (-OCH3).

Fig. 1

Design strategy for the synthesized compounds.

Fig. 2

Reaction Scheme of synthesized fluorinated diphenylamine chalcones.

Fig. 3

Antimicrobial activities of the chalone derivatives.

Fig. 4

Binding interaction between promising antimalarial compound B3 (A), B5 (B), B8 (C), and B9 (D) P. falciparum falcilysin protein (PDB ID: 7DI7).

Fig. 5

Time-dependent RMSD of P. falciparum falcilysin protein Cα atoms in complex with B3, B5, B8, and B9.

Fig. 6

Individual amino acids of RMSF of P. falciparum falcilysin protein Cα atoms in complex with B3, B5, B8, and B9.

Fig. 7

Protein–ligand contact analysis of MD trajectory.

Fig. 8

Graphical representation of % cytotoxicity of B3, B5, B7, B8 and B9 compounds.

Fig. 9

Interaction of ligand B5 (A, B & C) and ligand B7 (D, E & F) with the amino acids at the active site of the kinase domain of human Traf2- and Nck-interacting Kinase domain.

Fig. 10

Interaction of ligand B5 (A, B & C) and ligand B7 (D, E & F) with the amino acids at the active site of the CDK2/CyclinA domain.

Fig. 11

Time-dependent RMSD, RMSF of individual amino acids and time-dependent Hydrogen bond analysis of Human Traf2- and Nck-Interacting Kinase (PDB, ID: 2 × 7 F) and cyclin-dependent kinase (PDB, ID: 6GUE) Complexes with B5 and B7.

Fig. 12

Structure-activity relationship of the synthesized compounds.