Acta Pharm. 66 (2016) 331-351
Original research paper
Simple approach to thieno[3,2-d]pyrimidines
as new scaffolds of antimicrobial activities
HEND N. HAFEZ, ABDEL-RHMAN B. A. EL-GAZZAR and
MAGDI E. A. ZAKI
1 Al-Imam
Mohammad Ibn Saud Islamic University (IMSIU), College
of Science, Department of Chemistry, P. O. Box 90950, Riyadh 11623, Kingdom of
Saudi Arabia
2 Photochemistry
Department, (Heterocyclic & Nucleosides Unit), National Research
Centre, Cairo, Egypt
Accepted February 25, 2016
Published online May 20,
2016
6¢-(4-Chlorophenyl)-spiro[cyclohexane-1,2¢-thieno[3,2-d][1,3]oxazin]-4¢(1¢H)-one (1) was synthesized and used as a starting material for the synthesis of a novel series of spiro compounds having biologically active sulfonamide (2a-e) and 3¢-(4-acetylphenyl)-6¢-(4-chlorophenyl)-1¢H-spiro[cyclohexane-1,2¢-thieno[3,2-d]pyrimidine-4¢(3¢H)-one (3). Compound 2a was used as a key intermediate for the synthesis of sulfonyl carbothioamide derivatives (4a-c). Also, compound 3 was used as an intermediate for the synthesis of 3¢H-spiro[cyclohexane-1,2¢-thieno[3,2-d]pyrimidin]-3¢-yl]phenyl}-2-imino-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives (5a-e), 3¢H-spiro[cyclohexane-1,2¢-thieno[3,2-d]pyrimidin]-3¢-yl]phenyl}-2-oxo-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives (6a-e), and 4-[(2Z)-3-substituted-arylprop-2-enoyl]phenyl-1¢H-spiro[cyclohexane-1,2¢-thieno[3,2-d]pyrimidine derivatives (7a-e). Cyclocondensation of 7a-e with hydrazine hydrate produced 6¢-(4-chlorophenyl)-3¢-[4-(5-substituted aryl-4,5-dihydro-1H-pyrazol-3-yl)phenyl]-1¢H-spiro[cyclohexane-1,2¢-thieno-[3,2-d]pyrimidin]-4¢(3¢H)-ones (8a-e), but with hydroxylamine hydrochloride afforded the corresponding isoxazoline derivatives (9a-e). Also, cyclocondensation by thiourea afforded 2-thioxo-1,2-dihydropyrimidin-4-yl)-phenyl-spiro-{cyclohexanethieno[3,2-d]pyrimidin}-4-one derivatives (10a-e). The new compounds were investigated for antimicrobial activity. Compounds 2c, 8b, c, 9b and 10b were the most potent ones against both Gram-negative and Gram-positive bacteria. Compound 8c exhibited higher antifungal activity towards the examined fungi with MIC of 1–2 µmol mL–1 compared to ketoconazole (MIC 2–3 µmol mL–1).
Keywords: thieno[3,2-d][1,3]oxazin]-4¢-one, thieno[3,2-d]pyrimidines,
N-nucleophiles, spiro-thieno[3,2-d]pyrimidine, ring transformation, antimicrobial