Design, Synthesis, and Biological Activity Evaluation of 5-Aryl-cyclopenta[c]pyridine Derivatives

Abstract

Taking the natural product cerbinal as the lead compound, 30 novel 5-aryl-cyclopenta[c]pyridine derivatives were designed and synthesized based on the previous bioactivity studies of the cyclopenta[c]pyridines. The modification of the position-5 of compound 2 was achieved by amination, bromination, and cross coupling using cerbinal as the raw material. The results of the bioactivity tests demonstrated that partial compounds exhibited superior activity against plant viruses compared to compound 2. Compounds 4g and 4k showed higher anti-TMV activity levels than commercial varieties of ribavirin at concentrations of 500 and 100 μg/mL. In particular, compound 4k, which contained a m-methoxyphenyl substitution, displayed the most potent anti-TMV activity in vivo (inactivation effect 51.1 ± 1.9%, curative effect 50.7 ± 3.6%, protection effect 53.8 ± 2.8% at 500 μg/mL) The toxicological experiments also revealed that compound 4k exhibited low toxicity to zebrafish. Additionally, molecular docking results indicated that access to the benzene ring enhanced the binding affinity of these derivatives for TMV receptor proteins. Furthermore, studies on the insecticidal and fungicidal activities of these derivatives showed that most of the compounds exhibited good larvicidal efficacy against Plutella xylostella and broad-spectrum fungicidal activities. Notably, compound 4i (3,4,5-trifluorophenyl) displayed an outstanding inhibition ratio of 91.9% against Sclerotinia sclerotiorum, 75% against Botrytis cinerea, and 62.5% against Phytophthora infestans at a concentration of 50 μg/mL. These results suggest that 5-aryl-cyclopenta[c]pyridine derivatives could serve as promising candidate agents for antiviral, insecticidal, and fungicidal applications in agricultural production.