Farghaly A O, Moharram A M
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Faculty of Science, Assiut University, Egypt.
Boll Chim Farm. 1999 Jun;138(6):280-9.
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.
合成了一系列2-[(N,N-二取代硫代氨基甲酰硫基)甲基]喹唑啉酮9a-g、10a、10d、11a-d和12a，并评估了它们对多种真菌的潜在抗真菌活性。通过二取代二硫代氨基甲酸钾盐8a-g与相应的2-溴甲基-4(3H)-喹唑啉酮4或3-芳基-2-氯甲基-4(3H)-喹唑啉酮5-7反应来实现目标化合物的合成。二硫代氨基甲酸衍生物由适当的胺、醇性氢氧化钾溶液和二硫化碳通过一步反应合成。薄层色谱法和元素分析确定了合成化合物的纯度，其结构通过红外光谱和1H-核磁共振光谱得到证实。选择2-甲基-4(3H)-喹唑啉酮2（2-溴甲基中间体4的前体）作为详细光谱研究的代表性实例，除了HH COSY、APT和1H13C HETCOR光谱外，还包括300 MHz 1H-和13C-核磁共振，目的是确定相关化合物光谱数据的正确归属。合成的二取代二硫代氨基甲酸盐9a-g、10a、d、11a-d和12a以及作为参考药物的托萘酯和克霉唑，在2%和5%浓度下对23种致病真菌进行体外测试。研究表明，化合物9a表现出广谱抑制活性，对测试的真菌分离株优于或等同于参考药物。化合物9e对念珠菌属表现出选择性抑菌活性，化合物9g对小孢子菌属以及须癣毛癣菌也表现出抑菌活性。一般来说，可以推测与临床使用的硫代氨基甲酸盐化合物托萘酯相比，一些合成的二硫代氨基甲酸盐衍生物表现出广谱抗真菌活性，并且对念珠菌属和茄病镰刀菌也表现出与克霉唑相当的活性。
