Molecular docking, pharmacokinetic studies, and in vivo pharmacological study of indole derivative 2-(5-methoxy-2-methyl-1H-indole-3-yl)-N′-[(E)-(3-nitrophenyl) methylidene] acetohydrazide as a promising chemoprotective agent against cisplatin induced organ damage

Abstract

Cisplatin is an efficient anticancer drug against various types of cancers however, its usage involves side effects. We investigated the mechanisms of action of indole derivative, 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene] acetohydrazide (MMINA) against anticancer drug (cisplatin) induced organ damage using a rodent model. MMINA treatment reversed Cisplatin-induced NO and malondialdehyde (MDA) augmentation while boosted the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD). The animals were divided into five groups (n = 7). Group1: Control (Normal) group, Group 2: DMSO group, Group 3: cisplatin group, Group 4: cisplatin + MMINA group, Group 5: MMINA group. MMINA treatment normalized plasma levels of biochemical enzymes. We observed a significant decrease in CD4+COX-2, STAT3, and TNF-α cell population in whole blood after MMINA dosage. MMINA downregulated the expression of various signal transduction pathways regulating the genes involved in inflammation i.e. NF-κB, STAT-3, IL-1, COX-2, iNOS, and TNF-α. The protein expression of these regulatory factors was also downregulated in the liver, kidney, heart, and brain. In silico docking and dynamic simulations data were in agreement with the experimental findings. The physiochemical properties of MMINA predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS and inflammation.

Prevention of Testicular Damage by Indole Derivative MMINA via Upregulated StAR and CatSper Channels with Coincident Suppression of Oxidative Stress and Inflammation: In Silico and In Vivo Validation

“…The detail of compound synthesis and biological characterization has been reported. The compound was fully characterized by the spectral data and details are published [ 31 ] and included in Supplementary File S1 . Compound (MMINA), with para dimethylaminophenyl substitution, was found to have the highest antioxidant activity.…”

“…A dosage of 12 mg/kg body weight was selected according to previous literature to induce tissue damage [ 33 , 34 ]. A 25 mg/kg body weight dose of MMINA was selected based on our previous work [ 31 ].…”

“…Novel indole derivative, 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N’-[(E)-(3-nitrophenyl) methylidene] acetohydrazide (MMINA) was reported to have highly significant antiinflammatory and antioxidant activities as well as analgesic properties [ 30 ]. In our previous investigation, we observed a promising chemoprotective effect of MMINA against CDDP-induced organ injury by modulating antioxidant stress and regulating the expression of various signal transduction pathways involved in inflammation, i.e., NF-κB, STAT-3, IL-1, COX-2, iNOS, and TNF-α, in the kidney, liver, brain, and heart [ 31 ].…”

Sulindac acetohydrazide derivative attenuates against cisplatin induced organ damage by modulation of antioxidant and inflammatory signaling pathways

“…Whole blood was collected by cardiac puncture for the investigation of STAT3, TNF-α, and COX-2 expression by flow cytometry as described 45 .…”

Cisplatin for cancer therapy and overcoming chemoresistance

“…The cisplatin-treated cancers are attenuated with the suppression of tumorigenesis and metastases [ 2 ]. However, the biological applications of cisplatin are limited to eliminating the cancers because the average morbidity and mortality statistics are high [ 3 ], which may be due to prolonged usage that influence tumour adaptability [ 4 ] drug efflux [ 5 ] or acclimatisation in various biochemical [ 6 ] and immune networks [ 7 ] that modulate cancer -induced pathophysiology with widespread toxicity in the organs [ 8 ].…”