Microwave-assisted synthesis of potent PDE7 inhibitors containing a thienopyrimidin-4-amine scaffold

Sánchez, Aránzazu; Meneses, R.; Minguez, Jose M.; Núñez, Araceli; Castillo, Rafael R.; Filace, Fabiana; Burgos, Carolina; Vaquero, Juan J.; Alvárez‐Builla, Julio; Cortés-Cabrera, Álvaro; Gago, Federico; Terricabras, Emma; Segarra, Vı́ctor

doi:10.1039/c4ob00175c

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…Compound 7a was prepared from methyl 3-aminothiophene-2-carboxylate 20 (157 mg, 1.0 mmol) using method A as a white solid (83 mg, 50% yield), mp 235–238 °C [lit. mp 242 °C] …”

Section: Methodsmentioning

confidence: 99%

“…41 2-Ethylthieno[3,2-d]pyrimidin-4(3H)-one (7e). 38 To synthesize 7e, intermediate 23e (170 mg, 0.8 mmol) was treated with 20 mL of 30% ammonium hydroxide aqueous solution and stirred for 6 h at rt. Excess ammonia was released at low temperature and liquid was removed at high temperature under vacuum to obtain 7e as a white solid (87 mg, 60% yield).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

et al. 2019

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Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 μM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 μM), selectivity over normal gut microflora, CC50s > 606 μM against mammalian cell lines, and acceptable stability in simulated gastric and intestinal fluid. Further optimization of 6a at C2-, N3-, C4-, and C7-positions resulted in a library of >50 compounds with MICs ranging from 3 to 800 μM against clinical isolates of C. difficile. Compound 8f (MIC = 3/6 μM) was identified as a promising lead for further optimization.

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“…Compound 7a was prepared from methyl 3-aminothiophene-2-carboxylate 20 (157 mg, 1.0 mmol) using method A as a white solid (83 mg, 50% yield), mp 235–238 °C [lit. mp 242 °C] …”

Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%