Design, Synthesis And Biological Evaluation Of Novel Quinazoline-2,4-Dione Derivatives As Potential Chitin Synthase Inhibitors

Chitin is an important component of the fungal cell wall which does not exist in plants and mammals. Chitin synthase(CHS) is a key enzyme in the biosynthesis of chitin, therefore inhibiting the catalytic activity of chitin synthase can prevent chitin biosynthesis, and thereby inhibit the growth of fungi. Chitin synthesis inhibitor has become one of the hotspots in developing antifungal agents as it is harmless to human.Quinazolin-2,4-diones possesses multiple biological activities such as anti-HIV, anti-tumor, anti-cancer, anti-virus, enhance immune and other physiological functions. In recent years, quinazoline-2,4-diones have been modified, but in most case, the new groups were introduced to the 1 or 3 position of quinazolinone. In this article, a series of 7-position substituted quinazolin-2,4-diones were designed and synthesized. Their activities against chitin synthase were tested by non-radioactive high-throughput detection method and their antifungal and antibacterial activities were measured as well. The main work was summarized as following:1、Synthesis of novel quinazoline-2,4-dione amides: 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid 106 was obtained by 2-amino dimethyl terephthalate as the starting material, via substitution, hydrolysis, cyclization, etc. The novel target product quinazoline-2,4-dione amides 110a-u were prepared from compound 106 which reacted with a series of intermediate 109a-u.2、Synthesis of novel quinazoline-2,4-dione derivatives containing fluorine amides moeity: R-nectar acetal 113 was prepared from mannitol as starting material, then compound 113 reacted with difluoro ethyl bromoacetate by Reformatsky reaction to give compound 2,2-difluoro-3-hydroxy-(2,2-dimethyl-1,3-dioxolan-4-yl) propanoate 114, which reacted with a series of amines to give intermediate 116. Finally the intermediate 116 combined with the quinazolin-7-carboxy-2,4-dione 106 by the condensation reaction to afford the final products 117a-t.3、The condition for preparation of target compounds were expolored, and the optimal reaction condition was obtained. One hundred and eleven compounds were synthesized in this thesis and among these compounds sixty-nine new compounds. The structures of the obtained compounds were confirmed by 1H NMR, 13 C NMR or HRMS.4、The chitin synthase inhibition activity of all the compounds were tested, and the results showed that some compounds exhibited good inhibition activity. Novel quinazoline-2,4-dione amide 110o(IC50 = 0.68 m M) exhibited weaker inhibition activity than that of Polyoxin B(IC50 = 0.19 m M). The novel quinazoline-2,4-dione fluorinated amides also showed chitin synthase inhibition activity to some extent. When the concentrations of compound 117 d and 117 o were 150 μg/m L, the inhibition rates were 46.2% and 46.3% respectively, so there is still a gap compared to Polyoxin B(78.0%).5. All the target products were screened for their in vitro activity against fungi and bacteria using the standard two folds serial dilution method dilution. The antifungal evaluation in vitro demonstrated that quinazoline-2,4-dione amides 110 h, 110 l, 110 r, 110 o showed equivalent or better antifungal activity compared to the control drug. The novel quinazoline-2,4-dione fluorinated amides compounds 117 c, 117 d, 117 e, 117 t had good antifungal activity, equivalent to Fluconazole and much better than Polyoxin B. The antibacterial evaluation in vitro showed that the target compounds have weak inhibition activity against bacterial. It is demostrated that these designed compounds have selective antifungal activity.