Design and characterization of a binary CT complex of imidazole-oxyresveratrol: exploring its pharmacological and computational aspects.

A new binary charge transfer (CT) complex between imidazole (IMZ) and oxyresveratrol (OXA) was synthesized and characterized experimentally and theoretically. The experimental work was carried out in solution and solid state in selected solvents such as chloroform (CHL), methanol (Me-OH), ethanol (Et-OH), and acetonitrile (AN). The newly synthesized CT complex (D1) has been characterized by various techniques such as UV-visible spectroscopy, FTIR, 1H-NMR, and powder-XRD. The 1:1 composition of D1 is confirmed by Jobs' method of continuous variation and spectrophotometric (at λmax 554 nm) methods at 298 K. The infrared spectra of D1 confirmed the existence of proton transfer hydrogen bond beside charge transfer interaction. These findings indicate that the cation and anion are joined together by the weak hydrogen bonding as N+-H-O-. Reactivity parameters strongly recommended that IMZ behaves as a good electron donor and OXA an efficient electron acceptor. Density functional theory (DFT) computations with basis set B3LYP/6-31G (d,p) was applied to support the experimental results. TD-DFT calculations gives HOMO (-5.12 eV) → LUMO (-1.14 eV) electronic energy gap (ΔE) to be 3.80 eV. The bioorganic chemistry of D1 was well established after antioxidant, antimicrobial, and toxicity screening in Wistar rat. The type of interactions between HSA and D1 at the molecular level was studied through fluorescence spectroscopy. Binding constant along with the type of quenching mechanism, was investigated through the Stern-Volmer equation. Molecular docking demonstrated that D1 binds perfectly with human serum albumin and EGFR (1M17) and exposes free energy of binding (FEB) values of -295.2 and -283.3 kcal/mol, respectively. The D1 fits successfully into the minor groove of HAS and 1M17, the results of molecular docking show that the D1 binds perfectly with the HAS and 1M17, the higher value of binding energy shows stronger interaction between HAS and 1M17 with D1. Our synthesized complex shows good binding results with HAS compared to 1M17.Communicated by Ramaswamy H. Sarma.

Biochemical and histopathological analysis after sub-chronic administration of oxyresveratrol in Wistar rats.

Oxyresveratrol (OXY) is a naturally occurring phenolic compound; however, there are no toxicity studies reported on its long term use. The aim of our work was to demonstrate the evaluation of acute and sub-chronic toxicity of oxyresveratrol in rats to assess its safety profile. To evaluate the LD50 value, 2000 mg/kg of oxyresveratrol was administered to Wistar rats by oral gavage. For sub-chronic toxicity assessment, 80 Wistar rats were randomly divided into four groups (10 animal/sex/group) and oxyresveratrol administered at a dose of 50, 100, 150 mg/kg/day by oral gavage. Bodyweight, food, and water consumption were monitored every week. At the end of the experiments, biochemical and hematological parameters were analyzed. Gross and microscopic organ analyses were also carried out. LD50 of oxyresveratrol was greater than 2000 mg/kg sub-chronic administration of oxyresveratrol did not influence any mortality. Doses of 50 and 100 mg/kg of oxyresveratrol did not produce any sign of toxicity. However, the 150 mg/kg oxyresveratrol group depicted changes in multiple biochemical and hematological parameters with changes in the pathology of cardiac, hepatic, and renal tissues when compared with control. Therefore, no observed adverse effect level (NOAEL) of oxyresveratrol was observed to be 100 mg/kg per day for both male and female rats.

Development of a Lung Cancer Model in Wistar Rat and In Silico Screening of its Biomarkers.

BACKGROUND: Cancer is usually caused by three factors: Nutrition, inflammation and cigarette smoke. This study on rat experimental models would enable us to understand the mechanism of lung cancer caused by NNK to which humans are continuously exposed, help us understand possible molecular targets, and assist in designing drugs for humans against lung cancer. AIM: A lung cancer model was developed by administering tobacco-specific carcinogen: NNK [4- methylnitrosamino)-1-(3-pyridyl)-1-butanone] to male Wistar rats for 24 weeks. Furthermore, in silico approach was followed to screen the molecular targets. METHODS: A method was established in which subcutaneous and intraperitoneal injections of NNK were administered to male Wistar rats simultaneously. For authentication of lung cancer in vivo, we performed molecular docking simulations with protein biomarkers: Cox-2, p53, p38 MAPKs and EGFR using Hex-Discovery Studio, Schrödinger-maestro software. RESULTS: Lung morphology and histopathology indicated the initiation of bronchiolar epithelial hyperplasia and squamous dysplasia in the cancer 1 group after 16 weeks of NNK exposure. 66.66% incidence of squamous cell carcinoma (SCC) and 33.3% incidence of adenocarcinoma were observed in cancer 2 group after being exposed to NNK. Results indicated that the incidence of SCC and adenocarcinoma gradually increased from 66.66% to 85.71% in cancer 2 group and from 33.33% to 42.58% in cancer 3 group, respectively. Docking results indicate the total binding energy and glide energy of Cox-2, p53, p38 MAPKs, EGFR : 38.14, -211.58, -181.58, -213.05 Kcal/mol and -39.25, -32.16,-36.49, -40.19 Kcal/mol, respectively. CONCLUSION: Pulmonary adenocarcinoma model was developed by administering tobacco-specific carcinogen: NNK [4-methylnitrosamino)-1-(3-pyridyl)-1-butanone] to male Wistar rats in 24 weeks. In silico experiments confirmed EGFR to be the most potential target for NNK induced lung Cancer.