Indole-3-acetamides: As Potential Antihyperglycemic and Antioxidant Agents; Synthesis, In Vitro α-Amylase Inhibitory Activity, Structure–Activity Relationship, and In Silico Studies

Abstract

Indole-3-acetamides (1–24) were synthesized via coupling of indole-3-acetic acid with various substituted anilines in the presence of coupling reagent 1,1-carbonyldiimidazole. The structures of synthetic molecules were elucidated through different spectroscopic techniques including electron ionization-mass spectroscopy (EI-MS), 1H-, 13C NMR, and high-resolution EI-MS (HREI-MS). These compounds were screened for their antihyperglycemic and antioxidant potentials. All compounds displayed good to moderate inhibition against α-amylase enzyme with IC50 values ranging between 1.09 ± 0.11 and 2.84 ± 0.1 μM compared to the standard acarbose (IC50 = 0.92 ± 0.4 μM). Compound 15 (IC50 = 1.09 ± 0.11 μM) was the most active compound of the series and exhibited good inhibition against α-amylase; in addition, this compound also exhibited good antioxidant potential with IC50 values of 0.35 ± 0.1 and 0.81 ± 0.25 μM in 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-azino-bis­(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays, respectively. The binding interactions of synthetic molecules with the enzyme’s active site were confirmed via in silico studies. The current study had identified a number of lead molecules as potential antihyperglycemic and antioxidant agents.

Mono-n-butyl Malate-Derived Compounds from Camu-camu (Myrciaria dubia) Malic Acid: The Alkyl-Dependent Antihyperglycemic-Related Activity

“…Thus, the elevated blood glucose level was considered hyperglycemia . α-Amylase is responsible for the hydrolysis of complex polysaccharides into small oligosaccharides, and α-glucosidase finally converts all into glucose to be absorbed in the bloodstream …”

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

“…The consequences of SAR studies explained that compounds (4-(4methylphenyl)piperazin-1-yl)(5-methoxy-1H-indol-2yl)methanone (81.63 %), and (5-fluoro-1H-indol-2-yl)(4-(4hydroxyphenyl)piperazin-1-yl)methanone (85.6 %) had equivalent DPPH free radical scavenging activity as compared to standard drug Vitamin E (88.6 %). Khan et al [87] reported the synthesis and antioxidant activity of several aryl-substituted indole-3-acetamides (46). All the synthesized compounds evaluated for their antioxidant activity and result were exhibited good to moderate activity.…”

“…The 2,3‐dimethyl and 2,4‐dimethyl substituted indole derivatives exhibited high antidiabetic activity with IC 50 values 9.46±0.03 and 9.37±0.03 μM respectively in comparison with the reference drug acarbose 37.38±0.12 μM. Khan et al [87] . accounted the synthesis and antidiabetic property of various aryl‐substituted indole‐3‐acetamides ( 46 ).…”

Indole Derivatives Bearing Imidazole, Benzothiazole-2-Thione or Benzoxazole-2-Thione Moieties—Synthesis, Structure and Evaluation of Their Cytoprotective, Antioxidant, Antibacterial and Fungicidal Activities

“…The antioxidant properties of melatonin are probably due to the presence of the C-3 ethylamido side chain [ 14 ]. Also, synthetic indoles, bearing substitutes at the C-3 positions, are promising antioxidant agents [ 14 , 15 , 16 , 17 ]. Our previous study showed that gramine substituted by the pyrrolidinedithiocarbamate moiety has significant antioxidant properties [ 18 ].…”