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

摘要

A series of phosphorhydrazide (PHA) derivatives with the (X = O,S) P-NH alpha-NH beta-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 alpha-NH beta-C(O)(C4H4O) has more effect than the other compounds in inhibiting a-esterase. Docking analysis showed that hydrogen bonds were formed between the N-H-alpha protons of the (S) P-NH alpha-NH beta-C(S), (O)P-NH alpha-NH beta-C(S) and (O)P-NH alpha-NH beta-C(O) moieties with Gly323, Gly18 and Gly319 as well as the N-H-beta proton of the (S)P-NH alpha-NH beta-C(O) moiety and the AChE receptor site (Gly234). According to the QSAR model, the net charge of the N-H-alpha (Q(N(alpha))) nitrogen atom contributes an important electronic function in the inhibition of AChE. A high interrelationship between Q(N(alpha)) and Q(P) proved that the NH-P(X) moiety has a higher inhibitory activity than the N-HC(X) moiety.