Synthesis and Antifungal Activity of 2-Chloromethyl-1<i>H</i>-benzimidazole Derivatives against Phytopathogenic Fungi in Vitro

A series of 35 benzimidazole derivatives were synthesized from 2-chloromethyl-1<i>H</i>-benzimidazole in good yields. Their structures were characterized by ¹H and ¹³C NMR and HRESIMS. Antifungal activities of all of the synthesized compounds were evaluated against five phytopathogens fungi (<i>Cytospora</i> sp., <i>Colletotrichum gloeosporioides</i>, <i>Botrytis cinerea</i>, <i>Alternaria solani</i>, and <i>Fusarium solani</i>) using the mycelium growth rate method. Compound <b>4m</b> displayed strong growth inhibition of <i>C. gloeosporioides</i>, <i>A. solani</i>, and <i>F. solani</i> with IC₅₀ of 20.76, 27.58, and 18.60 μg/mL, respectively. Selective inhibition of <i>B. cinerea</i> instead of the other fungal pathogenes was observed with <b>7f</b> (IC₅₀ of 13.36 μg/mL), comparable to that of positive control, a commercial agricultural fungicide hymexazol (IC₅₀ of 8.92 μg/mL). Compound <b>5b</b> exhibited remarkable antifungal properties against <i>Cytospora</i> sp., <i>C. gloeosporioides</i>, <i>B. cinerea</i>, and <i>F. solani</i> with IC₅₀ values of 30.97, 11.38, 57.71, and 40.15 μg/mL, respectively; among the target fungi, <b>5b</b> was the most active compound and superior to the reference against <i>C. gloeosporioides</i> alone. Structure–activity relationship (SAR) data of these compounds are as follows: (1) introduction of the chlorine atom on para-position in the benzene ring help to increase activity (<b>4f</b> vs <b>4c</b>; <b>7f </b>vs<b> 7n</b>), (2) the sulfonyl group is critical for the inhibition of <i>C. gloeosporioides</i> (<b>5b</b> and <b>5c</b> vs <b>5a</b>), and (3) the unsubstituted benzene ring improve activity (<b>4m</b> vs <b>4n</b>, <b>4e</b> and <b>4a</b>). Thus, compounds <b>5b</b>, <b>4m</b>, and <b>7f</b> emerged as a new leading structure for the development of new fungicides