Novel indole based fused triazole-thiadiazole derivatives as anti-diabetic agents: <i>in vitro</i> and <i>in silico</i> approaches
Creators: name: Iqbal, Tayyiaba
name: Khan, Shoaib
name: Hussain, Rafaqat
name: Khan, Yousaf
name: Shoaib, Khurram
name: Rozeena
name: Saeed, Masab
name: Darwish, Hany W
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biophysics
subject: Biochemistry
subject: Neuroscience
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Infectious Diseases
subject: FOS: Health sciences

description: <b>Aim:</b> The current research presents novel library of indole derived fused triazole-thiadiazole derivatives (1–17) for treatment of diabetes mellitus. <b>Methods &amp; results:</b> These compounds were synthesized by treating 2-(1H-indol-3-yl)acetic acid with hydrazinecarbothiohydrazide followed by treating the resultant compound with substituted benzoic acid. Structural validation was achieved spectroscopically (<sup>1</sup>HNMR, <sup>13</sup>CNMR and HREI-MS). The synthesized compounds were subjected to biological evaluation to assess their potential as anti-diabetic. Molecular docking study was employed to investigate the binding interactions of these analogs with relevant proteins. ADMET analysis was used to predict their drug-like properties. Notably, compound-<b>10</b> (IC<sub>50</sub> = <b>1.27 ± 1.25</b> and <b>2.18 ± 2.45</b> μM) bearing <i>para</i>-substituted F atom exhibited the highest potency due to strong inhibitory interactions through hydrogen bonding. <b>Conclusion:</b> This study identifies promising compounds with anti-diabetic activity, paving the way for the treatment of diabetes mellitus. Diabetes is a chronic health disorder with a sustained increase in mortality rate by 3% reported in time frame of 2000 to 2019. Around 463 million cases of diabetes were reported in 2019 with a prediction of 700 million people suffering from DM by 2045 worldwide. An efficient route to hybrid indole derived fused triazole-thiadiazole derivatives was designed and successfully synthesized as anti-diabetic therapeutic agents. 2-(1H-indol-3-yl)acetic acid was stirred and mixed with hydrazinecarbothiohydrazide to synthesize indole based triazole intermediate. This intermediate was then treated with varied substituted benzoic acid to afford indole derived fused triazole-thiadiazole derivatives. Structural confirmation of these hybrid derivatives was conducted spectroscopically via <sup>13</sup>C-NMR, <sup>1</sup>H-NMR and HREI-MS. All the novel benzimidazole derived fused triazole-thiadiazole derivatives (1–17) were subjected to biological activity evaluation to study their <i>in vitro</i> anti-diabetic inhibitory potential and excellent results were obtained. Compound 17 (IC<sub>50</sub> = 1.92 ± 2.43 μM) exhibited strong potential against both enzymes in contrast to the standard drug. The structure-activity relationship (SAR) analysis reveals that the inhibitory potential of the compounds is significantly influenced by the number, nature (electron-donating or electron-withdrawing) and position of substituents around the phenyl ring. This SAR interpretation highlights the crucial role of substituent effects on modulating the biological activity of these compounds, providing valuable insights for further optimization and design of potent inhibitors. Molecular docking study was conducted to investigate the protein-ligand interaction (PLI) profile of the potent analogs, providing insights into their binding modes and interactions with the target protein. This study revealed the key residues and binding sites involved in the protein-ligand complex, further elucidating the structure-activity relationships and offering valuable guidance for the optimization of these compounds as potential therapeutics. An <i>in silico</i> ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) analysis was performed to assess the drug likeness properties of the potent analogs.