IN VITRO SCREENING OF ANTIMICROBIAL ACTIVITY AND STRUCTURE–ACTIVITY RELATIONSHIP STUDY OF A SERIES OF THIOUREA-CONTAINING COMPOUNDS

The global spread of antibiotic-resistance coupled with the paucity of new classes of antibiotics, indicates that there is an urgent need for discovery of new and more effective antimicrobials. Therefore, the aim of this study was to assess the antimicrobial activity of thirty-four thiourea derivatives against a range of reference strains of Gram-positive cocci, Gram-negative rods and yeasts, as well as to perform a structure-activity relationship study. A series of twenty-nine benzoylthioureas with various aliphatic and aromatic substituents at the thiourea moiety were appropriately synthesized. Afterwards, the substance that showed the best antimicrobial potential (N-(butylcarbamothioyl) benzamide; RTB168) was modified through the introduction of different substituents in the benzoyl ring, furnishing more three derivatives. Besides, RTB168 was converted to the corresponding guanidine and urea derivatives with the aim to confirm the importance of the thiourea moiety for the antimicrobial activity of this class of compounds. The activity of the thiourea derivatives on the growth of planktonic cells was evaluated by broth microdilution assay and the minimum inhibitory concentrations (MIC) were determined. In general, among all the 29 evaluated derivatives, the aliphatic compounds, mainly RTB 222 (Methyl), RTB 168 (Butyl) and RTB 203 (Hexyl), were more active than the aromatic ones against all bacteria and yeast utilized. Among Gram-positive bacteria, Streptococcus agalactiae ATCC 13813 showed the lower MIC value for RTB 168 (62.5 µg/mL), RTB203 (125.0 µg/mL) and RTB 222 (500.0 µg/mL), which indicates that the antimicrobial activity was sensible to the chain length. Besides, the isosteric replacement of sulfur by nitrogen or oxygen did not produce improvement in the antimicrobial effect against this bacteria, suggesting that the thiourea group could be considered a pharmacophore group. Except for the guanidine derivative (RTB 208), which showed weak activity against E. coli ATCC 25922 e K. pneumoniae ATCC 10031 (MIC = 500.0 µg/mL), none of the compounds inhibited the growth of the other Gram-negative species, with MIC ≥ 1000.0 µg/mL. Moreover, the compound RTB 168 presented moderate anti-Candida activity, with the MIC values against C. albicans ATCC 26790 (250.0 µg/mL) and C. tropicalis ATCC 28707 (250.0 µg/mL), as well as RTB 208 against C. tropicalis ATCC 28707 (250.0 µg/mL). These data indicate that thiourea derivatives are good candidates as lead compounds for the development of new antimicrobial drugs.