Synthesis and antifungal properties of certain 7-alkylaminopyrazolo[1,5-a]pyrimidines

A series of 7-alkylaminopyrazolo[1,5-alpha]pyrimidines (5-25) and one 7-alkylthiopyrazolo[1,5-alpha]pyrimidine (4) were synthesized from the corresponding 7-chloro precursors 3, which were prepared in turn from the 7-hydroxy analogues 2, obtained via condensation of 3-aminopyrazoles with acetoacetat...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1977-02, Vol.20 (2), p.296-299
Main Authors: Novinson, Thomas, Robins, Roland K, Matthews, Thomas R
Format: Article
Language:English
Subjects:
Administration, Topical
Animals
Antifungal Agents - chemical synthesis
Antifungal Agents - therapeutic use
Bacteria - drug effects
Cryptococcus neoformans - drug effects
Guinea Pigs
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Structure-Activity Relationship
Tinea - drug therapy
Trichophyton - drug effects
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Summary:A series of 7-alkylaminopyrazolo[1,5-alpha]pyrimidines (5-25) and one 7-alkylthiopyrazolo[1,5-alpha]pyrimidine (4) were synthesized from the corresponding 7-chloro precursors 3, which were prepared in turn from the 7-hydroxy analogues 2, obtained via condensation of 3-aminopyrazoles with acetoacetate esters, malonate esters, or acetylenedicarboxylate ester. Compounds 4-25 were found to inhibit Trichophyton mentagrophytes (in vitro). The degree of inhibition increased with increasing 7-alkylamino chain length up to C8 units and then began to decrease with longer chain lengths. Unsaturated chains were more fungitoxic than saturated chains, 5-methyl-7-oleylaminopyrazolo[1,5alpha]pyrimidine [22, R7=NH(CH2)8CH=CH(CH2)7CH3] being four times more inhibitory and 16 times more fungicidal (against T. mentagrophytes) than 5-methyl-7-n-octylaminopyrazolo[1,5-alpha] pyrimidine [11, R7=NH(CH2)7CH3]. Although 11 and 22 appeared to have some efficacy as topical antifungeal agents, when applied to T. mentagrophytes infections in vivo, both caused irritation (of abraded and unabraded guinea pig skin) as did compound 4 (R5=Me; R7=SC8H17).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00212a021