Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis.

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4 µg/mL for 24 and 48 h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Dietary Polyphenols: Review on Chemistry/Sources, Bioavailability/Metabolism, Antioxidant Effects, and Their Role in Disease Management.

Polyphenols, as secondary metabolites ubiquitous in plant sources, have emerged as pivotal bioactive compounds with far-reaching implications for human health. Plant polyphenols exhibit direct or indirect associations with biomolecules capable of modulating diverse physiological pathways. Due to their inherent abundance and structural diversity, polyphenols have garnered substantial attention from both the scientific and clinical communities. The review begins by providing an in-depth analysis of the chemical intricacies of polyphenols, shedding light on their structural diversity and the implications of such diversity on their biological activities. Subsequently, an exploration of the dietary origins of polyphenols elucidates the natural plant-based sources that contribute to their global availability. The discussion extends to the bioavailability and metabolism of polyphenols within the human body, unraveling the complex journey from ingestion to systemic effects. A central focus of the review is dedicated to unravelling the antioxidant effects of polyphenols, highlighting their role in combating oxidative stress and associated health conditions. The comprehensive analysis encompasses their impact on diverse health concerns such as hypertension, allergies, aging, and chronic diseases like heart stroke and diabetes. Insights into the global beneficial effects of polyphenols further underscore their potential as preventive and therapeutic agents. This review article critically examines the multifaceted aspects of dietary polyphenols, encompassing their chemistry, dietary origins, bioavailability/metabolism dynamics, and profound antioxidant effects. The synthesis of information presented herein aims to provide a valuable resource for researchers, clinicians, and health enthusiasts, fostering a deeper understanding of the intricate relationship between polyphenols and human health.

Design, synthesis, biological and computational screening of novel pyridine-based thiadiazole derivatives as prospective anti-inflammatory agents.

In this study, a novel series of pyridine-based thiadiazole derivatives (NTD1-NTD5) were synthesized as prospective anti-inflammatory agents by combining substituted carboxylic acid derivatives of 5-substituted-2-amino-1,3,4-thiadiazole with nicotinoyl isothiocyanate in the presence of acetone. The newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, and mass spectrometry. First, the compounds underwent rigorous in vivo testing for acute toxicity and anti-inflammatory activity and the results revealed that three compounds-NTD1, NTD2, and NTD3, displayed no acute toxicity and significant anti-inflammatory activity, surpassing the efficacy of the standard drug, diclofenac. Notably, NTD3, which featured benzoic acid substitution, emerged as the most potent anti-inflammatory agent among the screened compounds. To further validate these findings, an in silico docking study was carried out against COX-2 bound to diclofenac (PDB ID: 1pxx). The computational analysis demonstrated that NTD2, and NTD3, exhibited substantial binding affinity, with the lowest binding energies (-8.5 and -8.4, kcal/mol) compared to diclofenac (-8.4 kcal/mol). This alignment between in vivo and in silico data supported the robust anti-inflammatory potential of these derivatives. Moreover, molecular dynamics simulations were conducted, extending over 100 ns, to examine the dynamic interactions between the ligands and the target protein. The results solidified NTD3's position as a leading candidate, showing potent inhibitory activity through strong and sustained interactions, including stable hydrogen bond formations. This was further confirmed by RMSD values of 2-2.5 Å and 2-3Ǻ, reinforcing NTD3's potential as a useful anti-inflammatory agent. The drug likeness analysis of NTD3 through SwissADME indicated that most of the predicted parameters including Lipinski rule were within acceptable limits. While these findings are promising, further research is necessary to elucidate the precise relationships between the chemical structures and their activity, as well as to understand the mechanisms underlying their pharmacological effects. This study lays the foundation for the development of novel anti-inflammatory therapeutics, potentially offering improved efficacy and safety profiles.

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies.

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a-h were characterized using 1H NMR, 13C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7.34 ± 0.21 µM and 4.56 ± 0.18 µM, respectively. These results were compared to standard drugs, doxorubicin (IC50 = 12.420 ± 0.5 µM) and Hoechst 33342 (IC50 = 0.422 ± 0.02 µM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.

In Silico Drug Repurposing Studies for the Discovery of Novel Salicyl-AMP Ligase (MbtA)Inhibitors.

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug repurposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the repurposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. The literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein, we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. Virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (four antiviral, three anticancer, one CYP450 inhibitor, one ACE inhibitor, and one leukotriene antagonist), were repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top protein-ligand complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating antimicrobial resistance (AMR) and tuberculosis (TB).

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies.

Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.

Target prediction, computational identification, and network-based pharmacology of most potential phytoconstituent in medicinal leaves of Justicia adhatoda against SARS-CoV-2.

The current global epidemic of the novel coronavirus (SARS-CoV-2) has been labeled a global public health emergency since it is causing substantial morbidity and mortality on daily basis. We need to identify an effective medication against SARS-CoV-2 because of its fast dissemination and re-emergence. This research is being carried out as part of a larger strategy to identify the most promising therapeutic targets using protein-protein interactions analysis. Mpro has been identified as one of the most important therapeutic targets. In this study, we did in-silico investigations to identify the target and further molecular docking, ADME, and toxicity prediction were done to assess the potential phyto-active antiviral compounds from Justicia adhatoda as powerful inhibitors of the Mpro of SARS-COV-2. We also investigated the capacity of these molecules to create stable interactions with the Mpro using 100 ns molecular dynamics simulation. The highest scoring compounds (taraxerol, friedelanol, anisotine, and adhatodine) were also found to exhibit excellent solubility and pharmacodynamic characteristics. We employed MMPBSA simulations to assess the stability of docked molecules in the Mpro binding site, revealing that the above compounds form the most stable complex with the Mpro. Network-based Pharmacology suggested that the selected compounds have various modes of action against SARS-CoV-2 that include immunoreaction enrichment, inflammatory reaction suppression, and more. These findings point to a promising class of drugs that should be investigated further in biochemical and cell-based studies to see their effectiveness against nCOVID-19.Communicated by Ramaswamy H. Sarma.

Approaches for targeting the mycobactin biosynthesis pathway for novel anti-tubercular drug discovery: where we stand.

INTRODUCTION: Several decades of antitubercular drug discovery efforts have focused on novel antitubercular chemotherapies. However, recent efforts have greatly shifted toward countering extremely/multi/total drug-resistant species. Targeting the conditionally essential elements inside Mycobacterium is a relatively new approach against tuberculosis and has received lackluster attention. The siderophore, Mycobactin, is a conditionally essential molecule expressed by mycobacteria in iron-stress conditions. It helps capture the micronutrient iron, essential for the smooth functioning of cellular processes. AREAS COVERED: The authors discuss opportunities to target the conditionally essential pathways to help develop newer drugs and prolong the shelf life of existing therapeutics, emphasizing the bottlenecks in fast-tracking antitubercular drug discovery. EXPERT OPINION: While the lack of iron supply can cripple bacterial growth and multiplication, excess iron can cause oxidative overload. Constant up-regulation can strain the bacterial synthetic machinery, further slowing its growth. Mycobactin synthesis is tightly controlled by a genetically conserved mega enzyme family via up-regulation (HupB) or down-regulation (IdeR) based on iron availability in its microenvironment. Furthermore, the recycling of siderophores by the MmpL-MmpS4/5 orchestra provides endogenous drug targets to beat the bugs with iron-toxicity contrivance. These processes can be exploited as chinks in the armor of Mycobacterium and be used for new drug development.

Flavonoids as potential therapeutics against novel coronavirus disease-2019 (nCOVID-19).

Since time immemorial natural products have been a great source of medicine to mankind. The anti-viral activities from several ayurvedic herbal medicines (in the form of crude extract or fraction or isolated compounds) have been established but their effectiveness against coronavirus still needs to be explored. They can provide a rich resource of anti-SARS-CoV-2 drug candidates. In this paper, in-silico techniques have been used to identify the potential lead molecules against SARS-CoV-2. A list of flavonoids having anti-viral activity was prepared and evaluated against the selected target. Rhoifolin, 5,7-dimethoxyflavanone-4'-O-ß-d-glucopyranoside, baicalin, astragalin, luteolin, and kaempferol showed good binding affinity and thus these could be promising compounds. In-silico screening such as ADMET prediction has been performed which predicted that the selected flavonoids have good pharmacokinetics and pharmacodynamics properties. Molecular dynamics simulation studies and MM-PBSA binding free energy calculations showed luteolin to be a more effective candidate against viral protein Mpro. The novelty of the approach mainly rests in the identification of potent anti-viral natural molecules from natural products flavonoid group of molecules to be effective against the latest coronavirus infection.Communicated by Ramaswamy H. Sarma.