Synthesis, Molecular Docking and Mosquitocidal Efficacy of Lawsone and its Derivatives Against the Dengue Vector Aedes aegypti L. (Diptera: Culicidae).

BACKGROUND: Aedes aegypti is the primary vector of dengue, a significant public health problem in many countries. Controlling of Ae. aegypti is the biggest challenge in the mosquito control programe, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission. OBJECTIVE: To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1- phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis. METHODS: All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects. RESULTS: Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC<50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM). CONCLUSION: The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programe.

Geranii Herba as a Potential Inhibitor of SARS-CoV-2 Main 3CLpro, Spike RBD, and Regulation of Unfolded Protein Response: An In Silico Approach.

BACKGROUND: Since the first patient identified with SARS-CoV-2 symptoms in December 2019, the trend of a spreading coronavirus disease 2019 (COVID-19) infection has remained to date. As for now, there is an urgent need to develop novel drugs or vaccines for the SARS-CoV-2 virus. METHODS: Polyphenolic compounds have potential as drug candidates for various diseases, including viral infections. In this study, polyphenolic compounds contained in Geranii Herba were chosen for an in silico approach. The SARS-CoV-2 receptor-binding domain (RBD), 3CLpro (Replicase polyprotein 1ab), and the cell surface receptor glucose-regulated protein 78 (GRP78) were chosen as target proteins. RESULTS: Based on the molecular docking analysis, ellagic acid, gallic acid, geraniin, kaempferitrin, kaempferol, and quercetin showed significant binding interactions with the target proteins. Besides, the molecular dynamic simulation studies support Geranii Herba's inhibition efficiency on the SARS-CoV-2 RBD. We assume that the active compounds in Geranii Herba might inhibit SARS-CoV-2 cell entry through the ACE2 receptor and inhibit the proteolytic process. Besides, these compounds may help to regulate the cell signaling under the unfolded protein response in endoplasmic reticulum stress through the binding with GRP78 and avoid the SARS-CoV-2 interaction. CONCLUSIONS: Hence, the compounds present in Geranii Herba could be used as possible drug candidates for the prevention/treatment of SARS-CoV-2 infection.

Synthesis of a 1,2,3-bistriazole derivative of embelin and evaluation of its effect on high-fat diet fed-streptozotocin-induced type 2 diabetes in rats and molecular docking studies.

The embelin derivative 2a was synthesized with the 1,2,3-bistriazole and spectral data confirmed its structural identity. Anti-diabetic and anti-lipidemic effects were evaluated using HFD-STZ induced type 2 diabetic rats. The derivative 2a (30 mg/kg b wt.) supplementation significantly (P ≤ 0.01) normalized the changed biochemical parameters like fasting blood glucose (FBG), body weights, plasma insulin level, total cholesterol (TC), triglycerides (TG) and marker enzymes of carbohydrate metabolism. The derivative 2a (30 mg/kg) also showed a significant effect on oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (ITT). But 15 mg/kg dose of derivative 2a failed to show any significant effects in HFD-STZ induced type2 diabetic rats. Histopathology analysis substantiated the protective effect of this derivative 2a (30 mg/kg b wt.) on the ß-cells of the pancreatic, liver and adipose tissues in diabetic treated rats. Further, the expressions of PPARγ and GLUT4 were significantly enhanced in the epididymal adipose tissue. The HOMO and LUMO energies characterized the molecular stability of the derivative 2a with 6-311G++ (d, p) in DFT/B3LYP/LanL2DZ method using Gaussian09 program package. The molecular docking analysis also confirmed the activity of derivative 2a through hydrogen bond interaction with ARG 288, GLU 343, SER 342 and least energy value (-7.72 kcal/mol). Hence, the embelin-1,2,3-bis triazole derivative 2a (30 mg/kg) enhanced the activity of embelin and might be acting as a suitable drug for type 2 diabetes, obesity and its complications.