Calorimetry and structure-activity relationships for a series of antimicrobial hydrazides

摘要

This paper presents some recent developments on the use of quantitative structure-activity relationships (QSAR) based on biological calorimetry. The calorimetric biological potency can be measured for structurally related compounds whose activity would not be easily determined with less accurate and precise methods. A series of antimicrobial hydrazides was assayed against two different cultured cell systems, Escherichia coli and Saccharomyces cerevisiae. The direct demonstration of a similar mode of action for the two biological systems was achieved with the use of calorimetry. The measured values were described in terms of 3D molecular interaction fields (MIF) by means of a recently developed GRID independent method (GRIND). The aim of this approach is to allow the analysis of a large number of quantitative descriptors by using chemometric tools such as partial least squares (PLS). The correlation between chemical structures and changes in bioactivity is described without the need for 3D molecular alignment according to a suitable conformational bioactive template. The proposed model for these molecular interaction fields has revealed the importance of the stereo-electronic properties on the cells metabolism. Throughout this paper, we describe the usefulness of the same cell systems in disclosing partitioning behaviour of study hydrazide antimicrobials employing the diffusion technique of Taylor-Aris. Since this variable may be of utility in pharmacokinetic studies, we have modelled and predicted it based on computed MIF and multivariate statistics by a procedure called GRID/VolSurf. This result was achieved with a small number of VolSurf descriptors encoding a balanced range of hydrophilic-lipophilic properties. (C) 2004 Elsevier B.V. All rights reserved.