Design, Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs

Abstract

A series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., 1 H-NMR, 13 C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC 50 4.7 μM. 10A19, with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC 50 8.8 μM. IC 50 values of the remaining compounds ranged from 9.2 to 73.6 μM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB -4TZK and peptide deformylase PDB -3E3U. A suitable single crystal for one of the active compounds, 10A12, was generated and analysed to further confirm the structure of the compounds.

Tetrahydroisoquinoline based 5-nitro-2-furoic acid derivatives: a promising new approach for anti-tubercular agents

“…Our recently published work provides detailed procedures for synthesizing up to intermediate 10 . 29 Finally, the target molecules NFT-1 to NFT-26 were synthesized from 9(a–z) by treating with 5-nitrofuran-2-carboxylic acid via an acid-amine coupling reaction using HOB t , EDC·HCl, and DIPEA in DMF at 25 °C. In 1 H NMR, the disappearance of one proton of –NH 2 from around 4.5 to 4.8 ppm and the appearance of an additional new amide proton at around 11 ppm confirm the formation of carbohydrazide.…”

“…Apart from this, a few modern reports also suggested that the putative mode of action of antimycobacterial tetrahydroisoquinoline derivatives is through inhibition of InhA of MTB. 29,36 Based on these reported facts and rationale, targeting the InhA enzyme followed by disruption of mycobacterial cellular homeostasis may be the appropriate strategy for the current molecular docking study and hence we have chosen Mycobacterium tuberculosis InhA (PDB ID: 4OHU), for the docking studies of the titled compounds.…”

“…2). 29 Nitrofuranyl derivatives have been identified by Yempala et al as anti-tubercular agents. Most of the compounds demonstrated potent MICs against Mtb H37Rv in the range of 0.17 to 0.0072 mM.…”

“…30 We have recently reported THIQ-based anti-TB agents. 29 Inspired by their promising results, we hybridized THIQ with NF and reported the current amide derivatives. We noticed that our current work was very fruitful and resulted in much more potent anti-TB agents compared to our previously reported work.…”

“…We noticed that our current work was very fruitful and resulted in much more potent anti-TB agents compared to our previously reported work. 29 In Fig. 4, the design strategy for potential target molecules is shown.…”