An Efficient Method for the Synthesis and In Silico Study of Novel Oxy-Camalexins.

Abstract

Methoxycamalexins are close structural derivatives of the indolic phytoalexin Camalexin, which is a well-known drug lead with an antiproliferative and antioxidant profile. 6-methoxycamalexin, 7-methoxycamalexin, and 6,7-dimethoxycamalexin are natural bioactive products, and there is significant interest in the development of efficient methods for the synthesis of structurally related analogues. Herein, we describe an efficient and high-yielding method for the synthesis of variously substituted hydroxy-, bezyloxy, and methoxycamalexins. A set of methoxy-, hydroxy-, and benzyloxy-indoles were successfully amidoalkylated with N-acyliminium reagents derived in situ from the reaction of thiazole or methylthiazoles with Troc chloride. Eleven novel N-acylated analogues were synthesized, with yields ranging from 77% to 98%. Subsequent oxidative reactions with o-chloranil or DDQ led to 10 novel oxy-camalexins in 62-98% yield. This two-step approach allowed the synthesis of two 4,6-dimethoxy camalexins, which are difficult to obtain using published methods. The structure of the obtained products was unequivocally determined by ¹H-, ¹³C{¹H}-, HSQC-NMR, FTIR, and HRMS spectral analyses. An in silico assay was carried out on the obtained products to assess their general toxicity and physicochemical properties, including their compliance with Lipinski's rule of five. The results indicate that all compounds have good potential to be developed as drugs or agrochemicals.