Investigation of the reactivity indices for the formation of substituted dinitroanilines and correlations to their dockings on α-tubulin of Plasmodium falciparum.

The local and global reactivity descriptors of substituted dinitroaniline analogues were investigated using M06-2X/6-31 + G(d,p) method. It was observed that NH ₂ (m = 3.53 eV; p = 3.70 eV) substituent conveyed the highest nucleophilic character on the benzene ring system than the other groups under study. For the substrates 4-substituted-1-chloro-2,6-dinitrobenzenes, the condensed to atom electrophilicity ([Formula: see text]) increases in the order COOCH ₃  > NO ₂  > F > SO ₃ H > CN > Cl > Br. The para substituted groups with the halogens follow the order of increasing electronegativity, F > Cl > Br. However, the nucleophilicity of the halo substituents of the products increases in the order, F > Br > Cl. Molecular docking simulations using the homology model with the crystallographic structure of zinc-induced bovine tubulin heterodimer (1JFF) as one of the templates reveal that the interactions between the tubulins of Plasmodium falciparum and dinitroaniline analogues are due to H-bonding. In general, the binding interaction is with the following residues: Met137, ARG64, Lys60, Glu183, Val4, His28, Cys171, Tyr224, Asn206, 228, Ile235, and Leu238. The pK _a s of the residue decrease as the ring activating power of the substituents increases from strongly activating to weakly activating groups. There is no evidence of intra or intermolecular H-bonding between Arg64 and Cys171. Electronegativity (χ) gives a better generic description of the dinitroanilines than any other parameters considered. Short-range hydrophobic interaction contributes to reduced binding affinities of the ligands. Graphical abstractReaction of substituted 2,6-dinitro chlorobenzene with diisopropylamine. Orbital interaction between the substrates and diisopropylamine in the formation of the dinitroanilines.