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PHYSICOCHEMICAL PROPERTIES AND ANTIMICROBIAL ACTIVITY OF NEW SPIROCYCLIC THIENO[2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Modesto de Candia, Claudia Altamura, Nunzio Denora, Saverio Cellamare, Manuel Nuzzolese, Danila De Vito, Leonid G. Voskressensky, Alexey V. Varlamov, Cosimo D. Altomare
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Abstract


A number of 6'-methylidene-2,3-dihydro-1H-spiro[pyridine-4,5'-thieno[2,3-d]pyrimidin]-4'(3'H)-one derivatives, obtained as major products of a domino reaction between 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidines and electron-deficient alkynes, were characterized for their acid-base properties and lipophilicity and evaluated for the antimicrobial activity against a number of clinical isolates of bacterial and fungal strains. The cytotoxicity against four tumor cell lines was also screened for some compounds. The dissociation constants (pKa) and partition coefficients (log P) in 1-octanol–water system were determined using a potentiometric technique. The negative difference between the observed and calculated log P values could be explained in the light of the conformational rigidity. Most of the studied compounds showed a moderate and selective activity against Gram-positive bacteria strains (S. agalactiae, E. faecalis, S. epidermidis), whereas did not exhibit any effect against Gram-negative bacteria and fungi at the maximum test concentration (500 μM). Implications of the physicochemical properties in modulating the antimicrobial activity and cytotoxicity of the examined spirocyclic thieno[2,3-d]pyrimidin-4(3H)-one derivatives are also discussed.

Keywords


spiro[pyridine-4,5'-thieno[2,3-d]pyrimidine]; antibacterial activity; cytotoxicity; dissociation constant; lipophilicity

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