Wang-OSO3H catalyzed one-pot sonochemical synthesis of 1,2,4-benzothiadiazine-1,1-dioxide derivatives: Their in silico / in vitro assessments against MtbCM

Abstract

The sonochemical synthesis, in silico assessment and in vitro MtbCM inhibitory activities of a series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are described. These compounds were synthesized via a one-pot two-step sonochemical method involving the Wang-OSO3H catalyzed reaction of 2-aminobenzenesulfonamide with aldehydes followed by treatment with NaHSO3 in the same pot. The reaction proceeded at room temp in pure water affording the desired products in good yields. The use of heterogeneous catalyst, common oxidant, water as a solvent and ultrasound as the source of green energy in addition to the mild conditions, shorter reaction time and simple operational procedure are the key features of this methodology. In silico studies suggested that most of the synthesized compounds interacted with the external surface pockets of the MtbCM (PDB: 2FP2) active site cavity. Indeed, a curved loop site was noted where these compounds were binding and aligned. Three compounds e.g. 3c, 3d and 3e interacted well with MtbCM via the -NHSO2- moiety of their 2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide ring showing a common H-bond with SER70. They also showed good (55–63%) inhibition of MtbCM in vitro when tested at 10 µM. According to the SAR study a 4-substututed phenyl ring was preferred over a 3- or 2-substutited phenyl moiety at the C-2 position and the 4-MeOC6H4 substituent at this position was most effective in terms of activity. On the other hand, mediocre to low activity was observed when a heteroaryl ring or the bulky 2-naphthyl moiety was present at the C-2 position. Based on in silico and in vitro studies along with the ADME predictions the 1,2,4-benzothiadiazine-1,1-dioxide derivatives 3c, 3d and 3e emerged as pre-hits for further pharmacological evaluations.