An ultrasound based greener approach to 1-chloropyrrolo[1,2-a]quinoxalines as potential anti-tubercular agents

Abstract

Compounds containing the 1-chloropyrrolo[1,2-a]quinoxaline framework were assessed against MtbCM (chorismate mutase) for the identification of possible anti-tubercular entities. These compounds were synthesized via the sonochemical chlorination of pyrrolo[1,2-a]quinoxalines using N-chlorosaccharin. The regioselective C-1 chlorination, mild and eco-friendly conditions, and decreased reaction time are the key aspects of the present ultrasound-assisted method, an application of which is also demonstrated. The molecular docking of synthesized compounds into the target protein MtbCM revealed that they were oriented in the loop region of MtbCM and mostly interacted with the residues in the periphery of the loop via hydrophobic interactions e.g. (i) pi-sigma with LEU130 and LEU65, (ii) pi-anion with ASP69 and (iii) pi-cation with ARG134. Furthermore, similar molecular alignment of -Cl group displaying a hydrophobic interaction with PRO66 was noted in case of majority of these compounds. The compound 3b, 3f, 3g and 3k showed better binding affinities with the order 3b > 3f > 3g > 3k indicating 3b as the best among them. This observation correlated the outcome of in vitro assay using MtbCM when 3b, 3f and 3g showed >50 % inhibition at 30 μM. The Structure-Activity-Relationship (SAR) suggested that the C-4 aryl/heteroaryl group seemed to be vital for the activity. Indeed, a p-substituent on the C-4 phenyl ring was found to be favorable for activities. The role of Cl group was also assessed via in vitro testing of compounds with and without –Cl group. With the IC₅₀ value 12.34 ± 0.76 μM for MtbCM, the compound 3b was also expected to exhibit acceptable pharmacokinetic properties.