Phosphorhydrazide inhibitors: toxicological profile and antimicrobial evaluation assay, molecular modeling and QSAR study

Abstract

A series of phosphorhydrazide (PHA) derivatives with the (X = O,S) P–NH_α–NH_β–C (X = O,S) skeleton (1–23) were synthesized and characterized by spectral techniques. A single crystal X-ray study of 4 and 21 provided confirmation of the hydrogen bonding structures. The synthesized compounds exhibited drastically reduced antibacterial activity against Gram-positive and -negative bacteria compared to the reference drugs. The insecticide activity of the PHAs appraised for the elm leaf beetle demonstrated that (CH₃O)₂(S)P–NH_α–NH_β–C(O)(C₄H₄O) has more effect than the other compounds in inhibiting α-esterase. Docking analysis showed that hydrogen bonds were formed between the N–H_α protons of the (S)P–NH_α–NH_β–C(S), (O)P–NH_α–NH_β–C(S) and (O)P–NH_α–NH_β–C(O) moieties with Gly323, Gly18 and Gly319 as well as the N–H_β proton of the (S)P–NH_α–NH_β–C(O) moiety and the AChE receptor site (Gly234). According to the QSAR model, the net charge of the N–H_α (Q_N(α)) nitrogen atom contributes an important electronic function in the inhibition of AChE. A high interrelationship between Q_N(α) and Q_P proved that the NH–P(X) moiety has a higher inhibitory activity than the NH–C(X) moiety.