Synthesis And Antifungal Activities Of Aromatic Amidines

Aromatic amidine derivatives exhibit several significant bioactivities, such as antiprotozoan, antitumor, anti-inflammatory, antivirus, fungicidal,bactericidal and herbicidal activities. Propamidine, belongs to aromatic diamidines, has been developed by us as a new fungicide for treating plant disease. Based on the works done before, novel arylamidines with azide group, 1,2,3-triazole moiety, 1,2,4-triazole moiety, linear arylamidines long aliphatic chain, and multivalent amidines were designed and synthesized according to the bioactive fragment combination, scaffold alteration, and multieffect drug design method. 69 novel compounds were synthesized. The bioactivities to several phytopathogenic fungi were tested in vitro and their protective effects were assayed in vivo.1. Four aromatic amidines with azide groups and 20 such compounds with 1,2,3-triazole were designed by bioactive fragment-composition method and synthesized. The bioassay results showed that several such aromatic amidines with1,2,3-triazole moieties showed favorable inhibition activities to Colletotrichum lagenarium, Helminthosporiun turcicumand Cytospora cmalldehurica in vitro, but were still less potent than the positive control Propamidine and Carbendazim. Structure-Activity Relationship analysis showed that compounds with phenyl rings attached to the triazole ring were more potent than ones with hydroxyl group. The results showed that the protective effect of compound 16 d to tomato gray mould was 90% in vivo, exceeding the positive control Carbendazim(with a inhibition rate of 85%) and comparative to Propamidine(92%). The protective effect of compounds 15 b and 17 a to cucumber anthracnose were 68% and 74% in vivo, both surpassing Carbendazim(61%) and Propamidine(60%). It could be concluded that the amidines with 1, 2, 3-triazole rings had better bioactivities in vivo than in vitro.2. Eleven arylamidines having 1,2,4-triazole moieties were designed and synthesized according to the method of bioactive fragment combination. The bioassay results showed that the inhibition rates of compound 25 g to C. lagenarium and B. cinerea were 77% and 61%; the inhibition rates of compounds 25 g and 25 i to C. cmalldehurica were 67% and 70% respectively, and compound 25 f showed an inhibition rate of 71% to H. turcicum under a concentration of 50 μg/m L, but none of the compounds were as potent as the positive control Propamidine and Carbendazim. The in vivo bioassay results showed that the protective effects of compounds 25 f, 25 g and 25 i were 63%, 72% and 67% to tomato gray mould, less than Propamidine(82%) and Carbendazim(87%), and 67%, 59%, 62% to cucumber anthracnose, less or comparative to Carbendazim(61%) and Propamidine(68%) under 200 μg/m L. The activities in vitro of the amidines with 1,2,4-triazole rings were weak but the protective efficacy of some compounds were comparative to Propamidine and Carbendazim.3. Arylamidines with long aliphatic chains were designed by scaffold hopping method and 19 of such kind of compounds were synthesized and characterized by NMR and MS spectra method. The bioassay results showed that the inhibition rates of compounds 31 a, 31 d, 31 i and 32 b to S. sclerotiorum were 87%、81%、82% and 90% respectively, including which, there were 8 compounds more potent than Propamidine(66%) but less potent Carbendazim(100%) under a concentration of 20 μg/mL. The inhibition rates of 31f、32b to C. lagenarium were 83% and 76%, better than Propamidine(57%) under 20 μg/m L. Under the same concentration, the inhibition rate of 31 f was 68% to G. zeae, less potent than the positive control.4. Six 4-azido phenylamindines, 6 arylamidines with 1, 2, 3-triazole fragment, and 3 tetramidines were synthesized according to the multivalent effect. The bioassay results showed that the diamidines linked by 1, 2, 3-triazole showed excellent bioactivities to the test pathogenic fungi superior to the ones with only a single amidine moiety. The inhibition rate of 36 a to was 68% to C. lagenarium, comparable with Propamidine(70%) and less than Carbendazim(90%) under a concentration of 50μg/mL. The activity of 36 e to B. cinerea was 79%, comparable with Carbendazim(76%) and less than Propamidine(88%). The most potent compound to H. turcicum was 36 b, with an inhibition rate of 67%, less than Propamidine(72%) and Carbendazim(89%). The inhibition rate of 36 d to H. turcicum was 63%, less potent than Propamidine(67%) and Carbendazim(78%). It could be demonstrated that the bioactivities can be improved obviously when several aromatic monoamidines conjugated by linking groups, however, no aromatic di or tetramidines having activities comparable with Propamidine and Carbendazim were found in this work.It is well known that aromatic diamidines have high agricultural antifungal activities. It was demonstrate in this paper compounds with high antifungal activities can also be obtained by fragment conjugation, scaffold hopping, multivalent effect and other effective molecular design method. Although no compounds much more potent than Propamidine and Carbendazim in vitro were found in this paper, some molecules showed obvious protective efficacy in vivo surpassed Propamidine and Carbendazim. Massive works have been done on the bioactivities of the aromatic diamidines. The further work should focus on the diamidines, by the variation of the length and type of the linking groups, to found compounds with good selectivity and bioactivities.