Studies in 3D molecular fields generally contain a large amount of data, some of which are redundant or not relevant. The program Volsurf, a quite fast method, is able to compress the relevant information present in 3D molecular structures into a few descriptors that represent the physicochemical properties. In this study eighteen p-substituted benzoic acid N-(5-nitrothiophen-2-yl)methylenehydrazides with antimicrobial activity were evaluated against multidrug-resistant Staphylococcus aureus, correlating the three-dimensional characteristics of the ligands with their respective bioactivities. Structures were obtained by CORINA program, and using a GRID force field, the following probes have been used to generate their corresponding 3D interaction energies (MIFs): water, DRY, carbonyl oxygen atom and amide NH group. Calculations using Volsurf resulted in a statistically consistent model with 48 structural descriptors showing that hydrophobicity is a fundamental property in the analyzed biological response. Results have shown the potential of studied compounds as alternatives to the treatment of infections caused by multidrug-resistant Staphylococcus aureus.