N-Unsubstituted 1,2-benzothiazine 1,1-dioxides: Pd-catalyzed one-pot sonochemical access and in silico / in vitro evaluation against MtbCM

Abstract

The Pd-catalyzed one-pot sonochemical synthesis followed by in silico and in vitro evaluation of a range of N-unsubstituted 1,2-benzothiazine 1,1-dioxide derivatives is reported. The synthesis involved ultrasound assisted coupling-cyclization of 2-iodobenzenesulfonamide with terminal alkynes in the presence of (PPh3)4Pd, CuI, ZnCl2 and Et3N to afford the expected products in 73-80 % yield. This is the first example of accessing N-unsubstituted 1,2-benzothiazine 1,1-dioxides via Pd-catalyzed coupling-cyclization strategy in a single pot. Moreover, the use of mild conditions and ultrasound as the source of green energy are the main features of this approach. In silico studies suggested that all the synthesized compounds interacted with the loop near the active site of Mtb chorismate mutase or MtbCM. Indeed, these compounds showed H-bonding with residues in the hinge region of the active site loop and the benzothiazine 1,1-dioxide moiety was responsible for H-bonding with GLU68, SER70 and GLY71 residues. Three compounds e.g. 3d, 3e and 3f interacted well with MtbCM via the aforementioned H-bonds and their orientations seemed to be influenced considerably by the effective non-H-bond interactions with LEU65 and PRO66. They also showed encouraging (54-62 %) inhibition of MtbCM in vitro when tested at 10 µM. The outcome of in silico and in vitro studies along with the ADME predictions identified compound 3c, 3d and 3e as pre-hits for further pharmacological study.