Role of Weak Molecular Interactions in the Mechanism of Action of a Series of Antihelmintics

Abstract

Different physicochemical properties such as solute-solute and solute-solvent in- teractions, tautomerism, lipophilicity and solubility in water were determined for a serie of 6,7-diaryl-pteridines in order to relate those properties with their nematocide action.

Introduction

The pharmacological response of a drug can be the result of a complex formation between the drug and the receptor. This complex is generally the result of several types of interactions such as hydro- phobic and electrostatic forces, hydrogen bonding and electron donor-acceptor complexes [1].

Previous works [2,3] have shown the nematocide activity for a serie of substituted 6,7-diaryl- pteridines (I) against different experimental models. Different structure-activity relationships (SARs) have been established for these compounds through neural networks [3].

Experimental

Synthesis and nematocide accion for the studied compounds were previously described [2,3].

Results and Discussion

For 18 substituted 6,7-diaryl-pteridines the following physicochemical properties were determined: polar and hydrogen bonding interactions with the solvent, solute-solute interactions, tautomerism, solubility in water and lipophilicity.

It was observed that only lipophilic interactions are related with the measured nematocide action (%R) for these drugs.

The logarithm of the chromatographic retention factor extrapolated to pure water, log k’_w, was used as a lipophilicity index. A typical ODS column and methanol-water as mobile phase were used. A lin- ear regression between log k’ and the Reichardt solvent parameter, ET(30), for binary methanol-water mixtures was used to obtain log k’_w by extrapolation. This procedure is generally more appropriate than extrapolate from a log k’ vs. % organic modifier plot since curvature is often observed [4].

The correlation matrix between % R (percentage of decrease in nematode concentration when 100 μg/ml of the drug in DMSO are used in in vitro assays) and log k’_w is shown below.

	%R	log k’w
% R	1.0000	0.6769
log k’w	0.6769	1.0000

This results indicate that 67.69% of the variance in the biological activity produced by changes in drug concentration can be explained by lipophilic interactions.