Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect ...components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.
Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively ...modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and nonhistone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus producing adverse issues, causing therapeutic resistance, and they have poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDAC inhibitor is generally accomplished on the basis of systematic highthroughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, or linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target. The objective of this review is to elucidate the potential targets' design strategies, biological activity, and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates the designing strategies of the potential target along with biological activity and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is important for overcoming side effects, drug resistance, and effective cancer control.
SARS-CoV-2, a new type of Coronavirus, has affected more millions of people worldwide. From the spread of this infection, many studies related to this virus and drug designing for the treatment have ...been started. Most of the studies target the SARS-CoV-2 main protease, spike protein of SASR-CoV-2, and some are targeting the human furin protease. In the current work, we chose the clinically used drug molecules remdesivir, favipiravir, lopinavir, hydroxychloroquine, and chloroquine onto the target protein SARS-CoV-2 main protease. Docking studies were performed using Arguslab, while Discovery Studio collected 2D and 3D pose views with the crystal structure of COVID-19 main protease in complex with an inhibitor N3 with PDB ID 6LU7. Computational studies reveal that all ligands provided good binding affinities towards the target protein. Among all the chosen drugs, lopinavir showed the highest docking score of -11.75 kcal/mol. The results from this molecular docking study encourage the use of lopinavir as the first-line treatment drug due to its highest binding affinity.
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This study aimed to decipher the encoded information within the molecular structure of a dataset of GSK-3β inhibitors through a comprehensive quantity structural-activity relationship ...(QSAR) investigation employing traditional physicochemical descriptors. Various statistical techniques were applied, encompassing linear methods such as Multiple Linear Regression (MLR) and Partial Least Squares (PLS), along with non-linear approaches such as Artificial Neural Networks (ANN). Rigorous validation using diverse statistical tools confirmed the models’ precision and predictability. The model exhibited exceptional statistical relevance, as evidenced by standard parameters: S-value (0.37), F-value (37.17), r (0.93), r2 (0.855), and r2CV (0.78). They assessed predictive power and robustness by involving specific statistical parameters. Key descriptors analyzed, including Verloop L (subs 2), Lipole Z component (whole molecule), and VAMP Dipole Z component, offered crucial insights into their respective contributions. This analysis implies that targeted modifications in the substitution pattern potentially enhance GSK-3β inhibitory activity significantly. The established model clarified how bioactivity depends on structure and offered valuable recommendations for creating new compounds with better inhibitory activity profiles against the GSK-3β enzyme.
Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and ...fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects.Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects.
A novel series of phenyl substituted azetidine containing 1, 2, 4‐triazole derivatives 7(a–j) were synthesized and characterized by IR, 1HNMR, 13CNMR, and mass spectroscopy. Synthesized 1, 2, ...4‐triazole derivatives were subsequently assayed in vitro to investigate their antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli using broth dilution method. Compounds 7c, 7d, and 7e exhibited potent inhibitory activities as compared to standard cefotaxime. Further, fluorescence spectral studies were also carried out to ascertain the antibacterial potential of compound 7c against two bacterial strains, that is, P. aeruginosa and S. aureus. In docking studies, all the compounds exhibited good docking scores between −12.04 and −11.36 kcal/mol and indicated that compounds could act through inhibition of bacterial DNA gyrase (PDB ID 3U2D). Among all, 7c has shown the maximum docking score and found in agreement to in vitro studies. In conclusion, synthesized 1, 2, 4‐triazole derivatives holds substantial caliber to be categorized as antibacterial agents.
New series of quinoxaline derivatives (4a–4h) were synthesized by treating 2‐chloro‐3‐hydrazinyl quinoxalin (3) with various anilines. Compound 3 was obtained from the 2,3‐dichloroquinoxaline 2 which ...was prepared from 4‐dihydroquinoxaline‐2,3‐dione (1). All synthesized compounds (4a–4h) were characterized by various spectral techniques, that is, IR, 1H‐NMR, mass spectroscopy, and elemental analysis and completion of reaction were confirmed by TLC. In vitro antimicrobial activity of synthesized compounds was evaluated using disc diffusion assay against gram‐positive and gram‐negative microbial strains, and then, the minimum inhibitory concentration and IC50 values of compounds were also determined. The results of antimicrobial study revealed that compounds 4e, 4g, and 4a were active and exhibited better inhibitory activities as compared with standard drug amoxicillin. Docking studies were performed by using Argus lab, and all the compounds exhibited good docking scores between −9.53 and −7.94 kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID‐4XE6). Among all compounds, 4e has shown the maximum docking score and found in agreement to in vitro studies.
The PPAR‐γ agonist enhances the insulin sensitivity and avoids the disorganized hyperglycemic by promoting the insulin guided cellular uptake of blood glucose. Therefore, in the present work PPAR‐γ ...has chosen as the target for the molecular docking study to design an effective agonist of the same. By this research work an effort has been made to prepare amide and urea series of 1, 3, 4‐thiadiazole derivatives as 4‐substituted‐N‐(5‐(4‐(1‐piperidino)1‐piperidinyl)‐1,3,4‐(2‐thiadiazolyl)benzamide (4a‐f) and 1‐(4‐substitutedphenyl)‐3‐(5‐(4‐(1‐piperidino)1‐piperidinyl)‐1,3,4‐(2‐thiadiazolyl)urea (6a‐f). Both the docking score as well as the pharmacological animal study data has been suggested that the electron donating group containing compound 4f and 6f are most potent molecules for the antidiabetic activity close to the standard drug pioglitazone. It was further observed that the unsubstituted aromatic ring containing derivatives have also considerable effect (4a and 6a) than the electron withdrawing containing derivatives. After the comparison of biological data for amide and urea series, it was concluded that the urea (6a‐f) series is more effective than the amide series.
A one-pot protocol involving nitrile-derived amidoxime of 1,5-benzodiazepine to synthesize its novel pyrimidine derivatives using DMAD and DABCO catalyst under microwave conditions has been ...described. The antibacterial activity of the synthesized compounds was examined against Gram-positive
S. aureus
and Gram-negative
E. coli
using broth micro-dilution assay. Low IC
50
values for the synthesized compounds indicated their potential as antibacterial agents. Further, field emission scanning electron microscopic study and cell membrane leakage study ascertained that the test compounds have ability to cause cell lysis
via
bacterial cell membrane rupture and disintegration. In addition, molecular docking studies suggested that test compounds may act through bacterial DHFR inhibition.
Graphical Abstract
SYNOPSIS
Novel pyrimidine-incorporated 1,5-benzodiazepine analogues through its nitrile-derived amidoxime using one-pot domino approach have been synthesized. Structures of all the compounds were established through IR,
1
H
NMR,
13
C
NMR and mass spectral data. Further, antibacterial activity test was performed using broth micro-dilution assay and the probable mode of action of compound (
6
) was examined
via
field emission scanning electron microscopy (FE-SEM) and molecular docking studies.
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