2,1-Benzothiazine - (quinolin/thiophen)yl hydrazone frameworks as new monoamine oxidase inhibitory agents; synthesis, in vitro and in silico investigation

Abstract

Two series of new 2,1-benzothiazine derivatives have been synthesized by condensation of 4-hydrazono-1-methyl-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (5) with 2-chloroquinoline-3-carbaldehydes and acetylthiophenes to acquire new heteroaryl ethylidenes 7(a-f) and 9(a-k) in excellent yields. After characterization by FTIR, ¹H NMR, ¹³C NMR and elemental analyses, the newly synthesized analogues were investigated against monoamine oxidase enzymes (MAO A and MAO B). The titled compounds exhibited activity in the lower micromolar range among which 9e was the most potent compound against MAO A with IC₅₀ of 1.04 ± 0.01 μM whereas 9h proved to be the most potent derivative against MAO B with an IC₅₀ value of 1.03 ± 0.17 μM. Furthermore, in vitro results were further endorsed by molecular docking studies to determine the interaction between the potent compounds and the enzyme active site. These newly synthesized compounds represent promising hits for the development of safer and potent lead molecules for therapeutic use against depression and other neurological diseases.

Fig. 1. Structures of some biologically effective 2,1-benzothiazine derivatives.

Scheme 1. Synthetic route for the titled 2,1-benzothiazine derivatives.

Fig. 2. Isomeric forms of compounds 7(a–f) in solution resulting in duplicate peaks.

Fig. 3. Most potent MAO A inhibitory compounds.

Fig. 4. Most potent inhibitors of MAO B.

Fig. 5. Dual inhibitors of MAO A and MAO B.

Fig. 6. Interaction of 9e with MAO A protein.

Fig. 7. Interaction of 9h with MAO B protein.

Fig. 8. Current work compared to previous work.