Synthesis, Antitubercular Activity and DNA-binding Study of some 2-Amino-3-cyano-4H-chromen-4-ylphosphonates

Gulzar A Khan; Gowhar A Naikoo; Javeed A War; Umar Jan P; it; Mehraj Ud Din Sheikh; Imran Khan; Ratnesh Das

Abstract

Synthesis, Antitubercular Activity and DNA-binding Study of some 2-Amino-3-cyano-4H-chromen-4-ylphosphonates

Author(s): Gulzar A Khan, Gowhar A Naikoo, Javeed A War, Umar Jan Pandit, Mehraj Ud Din Sheikh, Imran Khan, Ratnesh Das

(2-Amino-3-cyano-4H-chromen-4-yl)-phosphonates 4a-e were synthesized on reacting substituted salicylaldehydes, malononitrile, and diethylphosphite via ultrasound irradiation in presence of catalytic amount of 4-Dimethylaminopyridine (DMAP). This protocol is an environmentally benign preparation and gives excellent yields of the target compounds (88-97%). The structures of new compounds were elucidated by spectroscopic techniques, including Fourier Transform Infra-Red (FTIR), Proton (¹H-NMR), Carbon-13 (¹³C-NMR), Phosphorus- 31 (³¹P-NMR) Nuclear Magnetic Resonance and Liquid Chromatography/High Resolution Mass Spectrometry (LC-HRMS). All the compounds were screened for antitubercular activity against Mycobacterium tuberculosis H₃₇ Rv using disc diffusion susceptibility method. The in vitro results indicate that all the compounds are potent. Among these 4d bearing nitro group at position C-2' is most effective and, gave a Minimal Inhibitory Concentration (MIC) value of 10 μg/ml in reference with Isoniazid at the same concentrations. DNA binding study of compound 4d with salmon milt DNA (sm-DNA) was confirmed with UV-Visible, fluorescence, cyclic voltammetry and molecular docking. It was revealed that 4d has a strong affinity towards sm-DNA and binds at DNA minor groove with a binding constant (K) 5.317 × 10⁵ mol^-1. Molecular docking calculations predicted strong affinity of 4d towards sm-DNA with a binding affinity (ΔG) -7.4 kcal mol^-1. Non-covalent interactions, H-bonding and van der Waals forces were predicted as the driving forces of interaction. The compound 4d exhibited selective affinity towards adeninethiamine (A-T) base pairs.