The Antimicrobial Acitvity and Quantitative Structure - Biological Activity Relationships Evaluation of Some Novel 2-Hydroxybenzamide Derivatives

Based on our studies of the biological activity of 2-hydroxybenzamide derivatives, we evaluated the antimicrobial activity of some novel compounds from this class (esters, hydrazides, hydrazones), against bacterial (Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Bacillus cereus) and fungical (Sacharomyces cerevisiae, Candida albicans) strains using the disc-diffusion method under standard conditions. It was found that all tested compounds present a good activity against the tested microorganisms and they were more active against Candida albicans. The established minimum inhibitory concentration (MIC) values were ranged between 10 -2 - 3.6·10 -4 mol/L and were used to obtain some quantitative structurebiological activity relationships using HyperChem 5.01 program for molecular modelling and conformational analysis. The established equations using different parameters present correlation coefficients statistically ensured.

2-Hydroxybenzamide and its derivatives have a long history as antimicrobial agents.It was found that 2hydroxybenzanilides, as well as O-substituted 2-hydroxybenzanilides, are a class of compounds with a large spectrum of biological activity [1,2,3].Synthesis of 2-hydroxybenzamides fused to another halogensubstituted aromatic ring has attracted wide spread attention due to their diverse application as antibacterial-, antiviral-, anti-inflammator y and analgesic agents.Salicylamide-O-acetic hydrazide and its hydrazones show anti-inflammatory and analgesic activity superior to salicylamide itself and lower ulcerogenic activity [4,5].Some ortho-substituted phenoxyalkanoic acids and their derivatives were synthesized [6,7] and tested for their antimicrobial activity [8].Therefore the search for new antimicrobial active compounds represents one of the most important directions of current medicinal chemistry.
The goal of this research was to evaluate the biological activity of some new synthesized compounds, 2-hydroxybenzamide derivatives [9,10], and to assess the relationships between the antimicrobial activity and the structure of these synthesized compounds.The influence of different substituents was also investigated.

Quantitative structure-activity relationships (QSAR)
Molecular modeling was achieved using HyperChem 5.01 for Windows software (MM+ program) and conformational analysis was established with Conformational Search program included in the same software package.

Results and discussions
The microbiological evaluation results are presented in table 2. MICs values remain unchanged after the first two days of incubation.
Analizing the MIC values obtained for the tested compounds, it can be observed that the substitution of the aniline aromatic ring from salicylanilide, with 2-CF 3 , provides compounds with bigger biological activity than the unsubstitued ones.Only in case of Candida albicans, the unsubstitued aniline aromatic ring possesses higher biological effect.The 3-CF 3 substitution of the aniline aromatic ring gives compounds more active against Bacillus cereus, Escherichia coli, Staphilococcus aureus, the rest of the microorganisms were easier inhibited by the unsubstitued salicylanilide.Comparing the activities obtained in case of 2-CF 3 , respectively 3-CF 3 , substituted aniline aromatic ring, it can be observed that the 2-CF 3subtituted derivatives present a bigger activity against Escherichia coli ºi Sacharomyces cerevisiae, meantime the 3-CF 3 -subtituted derivatives are more active against Staphilococcus aureus, Candida albicans.The 5-chloro-2hydroxy-N-phenyl-benzamide derivatives possess higher biological effect than salicylanilide, only Sacharomyces cerevisiae and Candida albicans species were easier inhibited by the salicylanilide itself.The MIC values obtained for ethyl esters were comparable to those for salicylanilide, but the hydrazides and hydrazones are more active comparatively to the control substance.
In order to establish the QSAR equations, the logarithm of the reversed MIC has been used.
Using minimum energy conformations the significant structural parameters were calculated [11] which are presented in table 3.

Table 1
THE TESTED COMPOUNDS

Table 2 THE
MINIMUM INHIBITORY CONCENTRATION (MIC) VALUES