Synthesis and antifungal activity of 3‐aryl‐1,2,4‐triazin‐6‐one derivatives

BACKGROUND As a result of resistance development in many plant‐pathogenic fungi to agricultural fungicides, there is an ongoing need to discover novel antifungal chemistries to help sustain efficient crop production. A fungicide screening program identified 3‐phenyl‐1‐(2,2,2‐trifluoroethyl)‐1,2,4‐triazin‐6(1 H )‐one (5) as a promising new starting point for further activity optimization. A series of analogs were designed, prepared and evaluated in growth inhibition assays using four plant‐pathogenic fungi. RESULTS Thirty nine analogs (compounds 5 to 43) were prepared to explore structure–activity relationships at R 1 and R 2 , and all targeted structures were characterized by 1 H NMR and MS. All compounds were in vitro tested against three ascomycetes [ Leptosphaeria nodorum , Magnaporthe grisea and Zymoseptoria tritici (syn. Mycosphaerella graminicola )] and one basidiomycete ( Ustilago maydis ) pathogen. When R 2 was trifluoroethyl, fungicidal activity was enhanced by a single electron‐withdrawing substitution, such as Br, Cl and CF 3 in the 3‐position at R 1 (compounds 9, 10 and 12), of which the 3‐bromo compound (10) was the most active (EC 50 = 0.08, averaged across four pathogens). More subtle activity improvement was found by addition of a second halogen substituent in the 4‐position, with the 3‐Br‐4‐F analog (20) being the most active against the commercially important cereal pathogen Z. tritici . Replacement of the R 2 haloalkyl group with benzyl, alkyl (e.g. n ‐butyl, i ‐butyl, n ‐pentyl) and, particularly, CH 2 ‐cycloalkyls (e.g. CH 2 ‐cyclopropyl, CH 2 ‐cyclobutyl) resulted in further activity enhancements against the ascomycete fungi, but was either neutral or detrimental to activity against U. maydis . One of the most active compounds in this series (41) gave control of Z. tritici , with an EC 50 of 0.005 ppm, comparable with that of the commercial strobilurin fungicide azoxystrobin (EC 50 0.002 ppm). CONCLUSIONS The present work demonstrated that the 3‐phenyl‐1,2,4‐triazin‐6‐ones are a novel series of compounds with highly compelling levels of antifungal activity against agriculturally relevant plant‐pathogenic fungi. © 2014 Society of Chemical Industry