Synthesis and in vitro antifungal activity of some N,N-disubstituted dithiocarbamic acid esters derived from 2-methylquinazolinones.
A series of 2-[(N,N-disubstituted thiocarbamoylthio)methyl]quinazolinones 9a-g; 10a; 10d; 11a-d and 12a were synthesized and evaluated for potential antifungal activity against a variety of fungal species. The synthesis of the target compounds was achieved by reaction of the potassium salts of disubstituted dithiocarbamic acids 8a-g and the respective 2-bromomethyl-4(3H)-quinazolinone 4 or 3-aryl-2-chloromethyl-4(3H)-quinazolinones 5-7. The dithiocarbamic acid derivatives were synthesized in a one step reaction from the appropriate amine, alcoholic potassium hydroxide solution and carbon disulfide. TLC and elemental analyses ascertained the purity of the synthesized compounds and their structures were confirmed by IR and 1H-NMR spectroscopy. 2-Methyl-4(3H)-quinazolinone 2, the precursor of the 2-bromomethyl intermediate 4, was selected as representative example for detailed spectroscopic investigations, including 300 MHz 1H- and 13C-NMR in addition to HH COSY; APT and 1H13C HETCOR spectra, with the aim of establishing correct assignment of the spectral data of related compounds. The synthesized disubstituted dithiocarbamates 9a-g; 10a,d; 11a-d and 12a as well as tolnaftate and clotrimazole, as reference drugs, were tested in vitro at 2 and 5% concentrations against 23 pathogenic fungi. The study revealed that compound 9a exhibited broad spectrum inhibitory activity that is superior or comparable to that of the reference drugs against the tested fungal isolates. Selective fungistatic activity against Candida species was elicited by compound 9e and against Microsporum species as well as Trichophyton mentagrophytes was also observed for compound 9g. As a general pattern it might be postulated that some of the synthesized dithiocarbamate derivatives showed broad spectrum antifungal activity as compared with tolnaftate, the clinically used thiocarbamate compound, and also exhibited comparable activity to clotrimazole against Candida species and F. Solani.
Farghaly
A O
AO
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Faculty of Science, Assiut University, Egypt.
Moharram
A M
AM
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology
D000935:Antifungal Agents; D011799:Quinazolines; D013859:Thiocarbamates