Synthesis, Molecular Docking and Biological Evaluation of N‐Substituted Indole Derivatives as Potential Anti‐Inflammatory and Antioxidant Agents

Abstract

Novel N-substituted Indole derivatives with various hetero-cyclic moieties were synthesized via an ethyl linker in order to obtain highly potent anti-inflammatory and antioxidant agents. The structure of the obtained chemical compounds was determined using IR, 1 H-NMR, and mass spectroscopy. Molecular docking was used to create selective and efficient COX-2 inhibitors from twelve novel indole derivatives (11a-c, 12a -c, 13a -c, and 14a -c). The compounds 13b and 14b had a high interaction energy, which inhibited the COX-2 enzyme. There is a relationship between anti-inflammatory activity and antioxidants, which is also defined by COX-2 inhibition, according to the mechanism of action. The Swiss ADME online programme was used to determine the drug-like properties of synthesized compounds. Two common and reliable methods were adopted to determine the antioxidant effect. In the DPPH assay, compounds 11a, 11b, and 14b, whereas compounds 11b, 13b, and 14b in the reducing power assay, were the most potent as compared with standard ascorbic acid. To evaluate the antiinflammatory effect at an acute and chronic level, the carrageenan-induced paw edema method along with the formalin-induced inflammation method were used both at low dose and high dose. From the collected results, compounds 13b and 14b were the most potent against acute and chronic inflammation. The results showed that the synthesized compounds are unique as anti-inflammatory and antioxidant agents, and that they could be useful for drug discovery in the future.

N-Derivatives of (Z)-Methyl 3-(4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylates as Antimicrobial Agents—In Silico and In Vitro Evaluation

“…All compounds have been assessed for their ADMET profile in ADMET Predictor version 10.4 provided by the Simulation Plus software package [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ...…”

“…Another promising scaffold is the indole ring attracting considerable attention because of its presence in proteins, amino acids, and bioactive alkaloids [ 19 ], and the wide range of biological activities of its derivatives [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], among which is antimicrobial activity [ 36 , 37 , 38 , 39 , 40 , 41 ]. Furthermore, indole ring is present in many approved drugs ( Figure 2 ).…”

Small Molecules as Anti‐inflammatory Agents: Molecular Mechanisms and Heterocycles as Inhibitors of Signaling Pathways

“…Compounds 30 and 31 were most potent against acute and chronic inflammation (Figure 18). [128] Mazzotta et al developed a library of 3-amino-alkylated indoles via an optimized Mannich green approach as antiinflammatory agents. Compounds 32 a-c with IC 50 values of 5.41, 4.22, and 6.3 μM exhibited strong inhibitory effects on nitric oxide production and interlinked NF-kB/ERK1/2 pathways (Figure 19).…”

Novel N -methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks

“…Searching the literature, it was found that indole is a nucleus of choice as a multi-target scaffold for the treatment of inflammation besides its antimicrobial and anti-oxidant activities 26–29 .…”

“…Thus, indole thiosemicarbazide derivatives showed both anticancer and anti-oxidant activity 26 , indole alkaloids obtained from Alstonia scholaris and Topsentia sponge showed antibacterial activity 4 , 31 . Indomethacin, the indole derivative, is considered one of the most promising synthetic drugs as an anti-inflammatory and analgesic agents 8 .…”