Discovery of new anti-diabetic potential agents based on paracetamol incorporating sulfa-drugs: Design, synthesis, α-amylase, and α-glucosidase inhibitors with molecular docking simulation.

Uncontrolled diabetes can lead to hyperglycemia, which causes neuropathy, heart attacks, retinopathy, and nervous system damage over time, therefore, controlling hyperglycemia using potential drug target inhibitors is a promising strategy. This work focused on synthesizing new derivatives via the diazo group, using a hybridization strategy involving two approved drugs, paracetamol and several sulfonamides. The newly designed diazo-paracetamols 5-12 were fully characterized and then screened for in vitro α-amylase and α-glucosidase activities and exhibited inhibitory percentages (IP) = 92.5-96.5 % and 91.0-95.7 % compared to Acarbose IP = 96.5 and 95.8 %, respectively at 100 µg/mL. The IC50 values of the synthesized derivatives were evaluated against α-amylase and α-glucosidase enzymes, and the results demonstrated moderate to potent activity. Among the tested diazo-paracetamols, compound 11 was found to have the highest potency activity against α-amylase with IC50 value of 0.98 ± 0.015 µM compared to Acarbose IC50 = 0.43 ± 0.009 µM, followed by compound 10 (IC50 = 1.55 ± 0.022 µM) and compound 9 (IC50 = 1.59 ± 0.023 µM). On the other hand, for α-glucosidase, compound 10 with pyrimidine moiety demonstrated the highest inhibitory activity with IC50 = 1.39 ± 0.021 µM relative to Acarbose IC50 = 1.24 ± 0.029 µM and the order of the most active derivatives was 10 > 9 (IC50 = 2.95 ± 0.046 µM) > 11 (IC50 = 5.13 ± 0.082 µM). SAR analysis confirmed that the presence of 4,5-dimethyl-isoxazole or pyrimidine nucleus attached to the sulfonyl group is important for activity. Finally, the docking simulation was achieved to determine the mode of binding interactions for the most active derivatives in the enzyme's active site.

Exploring the binding properties of DNA/BSA and cytotoxicity studies with new terpyridine-ester-based metal complexes (M = Fe(III), Ni(II), Cu(II) and Ru(III)) - A comparative analysis.

Many terpyridines and their metal complexes are known to exhibit remarkable potential for the interaction of biological targets. Notably, a subtle change in the structure of the ligand can influence these interactions significantly. In this regard, it would be very interesting to assess the binding affinity of functionalized molecules with DNA/BSA. In this work, a novel ester-based terpyridine (L) and the corresponding four metal complexes with Ni(II) (MC1), Cu(II) (MC2), Fe(III) (MC3) and Ru(III) (MC4) were prepared and structurally characterized using various spectroscopic and analytical techniques including the validation of molecular structures of ligand (L) and Ni(II)-Tpy complex (MC1). The EPR data demonstrate that MC1 is diamagnetic and other complexes (MC2-MC4) exhibit paramagnetic behavior. Additionally, the structures of ligands and metal complexes were determined using DFT studies and the same were utilized for the docking studies. Interestingly, MC3 and MC4 exhibit a predominant lowest binding energy of -9.62 Kcal/mol (with DNA) and -10.05 Kcal/mol (with BSA) respectively. The binding affinity of the ligand and its complexes with protein and DNA was evaluated by spectroscopic techniques. Notably, the cytotoxicity studies of L and MC1-MC4 were performed against the MCF-7 (human breast cancer) cell lines. The complex MC4 displayed great activity with an IC50 of 3.5 ±â€¯1.75 µM among all synthesized compounds and comparable with cisplatin.

A Comprehensive Update of Anti-COVID-19 Activity of Heterocyclic Compounds.

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.

New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors.

It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

Recent Developments in the Antimicrobial Potential of Some Nitrogenous Heterocycles and their SAR Studies: A Review.

BACKGROUND: Infection remains a significant global health concern, with millions of new cases and deaths occurring due to infectious diseases. Currently, chemoprophylaxis and chemotherapy are the primary treatments, but side effects and toxicities pose challenges. Pathogenic microorganisms have developed resistance to antimicrobial medications. Nitrogen containing heterocyclic scaffolds possess the potential in drug discovery and are explored in various fields like pharmaceuticals, cosmetics, and agrochemicals. To minimize antimicrobial drug resistance, there is a need to design potent, safer antimicrobial lead compounds with higher selectivity and minimal cytotoxicity. OBJECTIVES: The present review aims to outline several recent developments in medicinal chemistry aspect of nitrogenous heterocyclic derivatives with the following purposes: (1) To cast light on the recent literature reports of the last eight years ranging from 2015 to 2023 describing anti-microbial potential of nitrogen-containing heterocyclic derivatives which includes pyrazole, pyrazoline, imidazole, tetrazole and quinoline; (2) To brief the recent developments in the medicinal chemistry of nitrogenous heterocyclic derivatives that is directed towards their anti-microbial profile; (3) To summarize the complete correlation of structural features of nitrogenous heterocyclic molecules with the pharmacological action including in silico as well as mechanistic studies to provide thoughts accompanying the generation of lead molecules. METHODS: Antimicrobial potential of nitrogenous heterocyclic molecules has been displayed by relating the structural features of various lead candidates with their in vitro as well as in vivo antimicrobial outcomes. In contrast, in silico computational analysis from different articles also helped to predict the SAR of potent molecules. RESULTS: Nitrogen containing heterocycles are involved in a range of natural to synthetic analogues with keen antimicrobial potency. It is an emerging need to generate new nitrogenous heterocyclic molecules in order to tackle the drug resistance in micro-organisms with more targeted selectivity as well as specificity. CONCLUSION: To limit the side effects associated with them and to combat the microbes acquired resistance towards the current drug regimen, novel nitrogenous heterocycle based antimicrobial agents are essential to be developed. This review connects the structural units present in lead compounds with their promising antimicrobial action.

Antimicrobial, anticancer activities, molecular docking, and DFT/B3LYP/LANL2DZ analysis of heterocyclic cellulose derivative and their Cu-complexes.

In this study, novel Cu-complexes of heterocyclic cellulose which were synthesized via the reaction of carboxymethyl cellulose (CMC) from bagasse pulp with NH2NH2 to give hydrazide cellulose which easily reacted with CS2 to form salt and then cyclized in the presence of HCl to afford cellulose oxadiazole, or with hydrazine hydrate to give cellulose triazole. Furthermore, the cellulose oxadiazole and triazole moieties acting as chelating agents with metal ion Cu (II), and all synthesized compounds were examined for their spectral analysis to show the adsorption of Cu (II) on the surface of cellulose through intramolecular hydrogen bonding. Results illustrated that cellulose oxadiazole and Cu- cellulose oxadiazole exhibited antimicrobial activities more than triazole and Cu- cellulose triazole. Furthermore, anticancer results showed that both cellulose oxadiazole and triazole exhibited activity higher than Cu-cellulose oxadiazole and Cu-cellulose triazole, where the cellulose triazole showed the highest activity (IC50 = 58.7 µg/µL). Additionally, the docking simulation of the synthesized cellulose complexes with different proteins such as PDBID:3t88, PDBID:4ynt, PDBID:1tgh, PDBID:2wje, and PDBID:4hdq and shortage bond length to confirm the experimental results. Optimization of metal complexes utilized the DFT/B3LYP/LANL2DZ basis set to confirm the stability of these metals theoretically and their physical descriptors and FMO analysis.

Ultrathin TiS2@N,S-Doped Carbon Hybrid Nanosheets as Highly Efficient Photoresponsive Antibacterial Agents.

Nanobactericides are employed as a promising class of nanomaterials for eradicating microbial infections, considering the rapid resistance risks of conventional antibiotics. Herein, we present a pioneering approach, reporting the synthesis of two-dimensional titanium disulfide nanosheets coated by nitrogen/sulfur-codoped carbon nanosheets (2D-TiS2@NSCLAA hybrid NSs) using a rapid l-ascorbic acid-assisted sulfurization of Ti3C2Tx-MXene to achieve efficient alternative bactericides. The as-developed materials were systematically characterized using a suite of different spectroscopy and microscopy techniques, in which the X-ray diffraction/Raman spectroscopy/X-ray photoelectron spectroscopy data confirm the existence of TiS2 and C, while the morphological investigation reveals single- to few-layered TiS2 NSs confined by N,S-doped C, suggesting the successful synthesis of the ultrathin hybrid NSs. From in vitro evaluation, the resultant product demonstrates impressive bactericidal potential against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, achieving a substantial decrease in the bacterial viability under a 1.2 J dose of visible-light irradiation at the lowest concentration of 5 µg·mL-1 compared to Ti3C2Tx (15 µg·mL-1), TiS2-C (10 µg·mL-1), and standard antibiotic ciprofloxacin (15 µg·mL-1), respectively. The enhanced degradation efficiency is attributed to the ultrathin TiS2 NSs encapsulated within heteroatom N,S-doped C, facilitating effective photogenerated charge-carrier separation that generates multiple reactive oxygen species (ROS) and induced physical stress as well as piercing action due to its ultrathin structure, resulting in multimechanistic cytotoxicity and damage to bacterial cells. Furthermore, the obtained results from molecular docking studies conducted via computational simulation (in silico) of the as-synthesized materials against selected proteins (ß-lactamasE. coli/DNA-GyrasE. coli) are well-consistent with the in vitro antibacterial results, providing strong and consistent validation. Thus, this sophisticated study presents a simple and effective synthesis technique for the structural engineering of metal sulfide-based hybrids as functionalized synthetic bactericides.

Nitrophenylpiperazine derivatives as novel tyrosinase inhibitors: design, synthesis, and in silico evaluations.

A novel series of 4-nitrophenylpiperazine derivatives (4a-m) was designed and synthesized as potential tyrosinase inhibitors. Comprehensive characterization using 1H-NMR, 13C-NMR, CNH, and IR techniques was performed for all target compounds. Subsequently, the derivatives were evaluated for their inhibitory activity against tyrosinase. Among them, compound 4l, featuring an indole moiety at the N-1 position of the piperazine ring, exhibited a significant tyrosinase inhibitory effect with an IC50 value of 72.55 µM. Enzyme kinetics analysis revealed that 4l displayed mixed inhibition of the tyrosinase enzymatic reaction. Molecular docking was carried out in the enzyme's active site to further investigate the enzyme-inhibitor interactions. Based on the findings, compound 4l shows promise as a lead structure for the design of potent tyrosinase inhibitors. This study paves the way for the development of more effective tyrosinase inhibitors for potential applications in various fields.

Facile one-pot synthesis and in silico study of new heterocyclic scaffolds with 4-pyridyl moiety: Mechanistic insights and X-ray crystallographic elucidation.

4-Acetylpyridine 1 and malononitrile 2 were allowed to react in a 3MCRs with dimedone 3a or cyclohexa-1,3-dione 3b under reflux to afford 4-methyl-4-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-chromene derivatives 4a,b respectively. The mechanism of the reaction has been studied and the structures elucidated by analytical, spectral as well as X-ray crystallographic data. Heterocyclic compounds find widespread application in pharmaceutical and agrochemical products. Docking analyses were performed on the synthesized compounds to assess their binding modes with various amino acids of the target protein tubulin (PDB Code - 1SA0). The results indicated promising binding scores for compounds 4a and 4b, suggesting a strong affinity for the tubulin binding site. Finally, ADMET for the synthesized compounds 4a, 4b, 5, 8a and 8b were carried out. The drug likeness and pharmacokinetic properties of the prepared compounds were also evaluated. Notably, all of the novel compounds adhered to Lipinski's rule (Ro5) without any violations.

Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide-hydantoin hybrids.

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO2 hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with KIs values in the submicromolar to micromolar ranges. The salts 3a and 3b, followed by derivative 5, displayed the best inhibitory activity of all the evaluated compounds and their binding mode was proposed in silico. These compounds can also be considered interesting starting points for the development of novel pharmacophores for this class of enzyme inhibitors.

New oxadiazole and pyrazoline derivatives as anti-proliferative agents targeting EGFR-TK: design, synthesis, biological evaluation and molecular docking study.

Two new series of oxadiazole and pyrazoline derivatives were designed and synthesized as promising EGFR-TK inhibitors. The in vitro antiproliferative activity was studied against three human cancer cell lines; HCT116, HepG-2 and MCF7 using MTT assay. Compound 10c showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 1.82 to 5.55 µM, while proving safe towards normal cells WI-38 (IC50 = 41.17 µM) compared to the reference drug doxorubicin (IC50 = 6.72 µM). The most active candidates 5a, 9b, 10a, 10b and 10c were further assessed for their EGFR-TK inhibition. The best of which, compounds 5a and 10b showed IC50 of 0.09 and 0.16 µM respectively compared to gefitinib (IC50 = 0.04 µM). Further investigation against other EGFR family members, showed that 5a displayed good activities against HER3 and HER4 with IC50 values 0.18 and 0.37 µM, respectively compared to gefitinib (IC50 = 0.35 and 0.58 µM, respectively). Furthermore, 5a was evaluated for cell cycle distribution and apoptotic induction on HepG-2 cells. It induced mitochondrial apoptotic pathway and increased accumulation of ROS. Molecular docking study came in agreement with the biological results. Compounds 5a and 10b showed promising drug-likeness with good physicochemical properties.

Insights into nucleoside hydrolase from Leishmania donovani inhibition: A new bioaffinity chromatography-based screening assay and docking studies.

Leishmaniasis, a group of neglected infectious diseases, encompasses a serious health concern, particularly with visceral leishmaniasis exhibiting potentially fatal outcomes. Nucleoside hydrolase (NH) has a fundamental role in the purine salvage pathway, crucial for Leishmania donovani survival, and presents a promising target for developing new drugs for visceral leishmaniasis treatment. In this study, LdNH was immobilized into fused silica capillaries, resulting in immobilized enzyme reactors (IMERs). The LdNH-IMER activity was monitored on-flow in a multidimensional liquid chromatography system, with the IMER in the first dimension. A C18 analytical column in the second dimension furnished the rapid separation of the substrate (inosine) and product (hypoxanthine), enabling direct enzyme activity monitoring through product quantification. LdNH-IMER exhibited high stability and was characterized by determining the Michaelis-Menten constant. A known inhibitor (1-(ß-d-Ribofuranosyl)-4-quinolone derivative) was used as a model to validate the established method in inhibitor recognition. Screening of three additional derivatives of 1-(ß-d-Ribofuranosyl)-4-quinolone led to the discovery of novel inhibitors, with compound 2a exhibiting superior inhibitory activity (Ki = 23.37 ± 3.64 µmol/L) compared to the employed model inhibitor. Docking and Molecular Dynamics studies provided crucial insights into inhibitor interactions at the enzyme active site, offering valuable information for developing new LdNH inhibitors. Therefore, this study presents a novel screening assay and contributes to the development of potent LdNH inhibitors.

3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies.

Seven 3-styrylcoumarins were tested for antileishmanial activity against Leishmania (Viannia) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative 6 was the most active with an IC50 of 40.5 µM, and did not reveal any conspicuous toxicity toward mammalian U-937 cells. Therefore, it may have potential to be considered as candidate for antileishmanial drug development. Further, among several druggable Leishmania targets, molecular docking studies revealed that compound 6 had docking preference by the N-myristoyltransferase (Lp-NMT) of Leishmania panamensis, showing a higher docking score of - 10.1 kcal mol-1 than positive controls and making this protein as a presumably druggable target for this compound. On the other hand, molecular dynamics simulations affirm the docking hypothesis, showing a conformational stability of the 6/Lp-NMT complex throughout 100 ns simulation. Moreover, the molecular mechanics/Poisson-Boltzmann surface area method also support the docking findings, revealing a total free energy of binding of - 47.26 ± 0.08 kcal mol-1, and identifying through energy decomposition analysis that those key aminoacids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6. Altogether, coumarin 6 could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.

Chitosan-sulfonic acid-catalyzed green synthesis of naphthalene-based azines as potential anticancer agents.

Aim: This study focuses on advancing green chemistry in anticancer drug discovery, particularly through the synthesis of azine derivatives with a naphthalene core using CS-SO3H as a catalyst. Methods: Novel benzaldazine and ketazine derivatives were synthesized using (E)-(naphthalen-1-ylmethylene)hydrazine and various carbonyl compounds. The methods employed included thermal and grinding techniques, utilizing CS-SO3H as an eco-friendly and cost-effective catalyst. Results: The approach resulted in high yields, short reaction times and demonstrated catalyst reusability. Cytotoxicity tests highlighted compounds 3b, 11 and 13 as potent against the HEPG2-1. Conclusion: This study successfully aligns with the objectives of eco-conscious drug development in organic chemistry. Molecular docking and in silico studies further indicate the potential of these ligands as antitumor medicines, with favorable oral bioavailability properties.

The potential of some functional group compounds substituted 8-Manzamine A as RSK1 inhibitors: molecular docking and molecular dynamics simulations.

Cancer, an incurable global disease, demands urgent anti-cancer drug development. Marine alkaloids like Manzamine and its derivatives show promise as RSK inhibitors against cancer cell invasion. Replacing the hydrogen at the 8-position of Manzamine A with a hydroxyl group has been shown to significantly enhance its biological activity. In this article, we designed various functional group compounds (A1-A21) substituted 8-Manzamine A by docking, MM-GBSA, molecular dynamics (MD) simulation, and well-tempered metadynamics (WT-MetaD) simulations to evaluate their potential as RSK1 inhibitors. Ligands A1-A21 were docked in the RSK1 N-terminal kinase domain (PDB ID: 2Z7Q) using the Glide module. The calculation of binding energy was performed using Prime MM-GB/SA, while MD simulations were conducted with the Desmond module of Schrodinger suite 2023. Compound A5 exhibits the highest G-score (-7.01) compared to 8-Hydroxymanzamine A (-6.08). Additionally, compounds A6, A10, A12, A17, A11, A4, and A13 demonstrate increased activity against RSK1 when compared to both 8-Hydroxymanzamine A and Manzamine A. Residues LEU68, VAL76, LEU141, PHE143, LEU144, PHE150, ASP148, GLU191, and LEU194 of RSK1 protein play a key role in binding with ligands. An MD simulation of Compound A5 was carried out to explore the dynamic interactions within the protein-ligand complex. Furthermore, WT-MetaD simulations validated the docking study results and identified the most energetically favored conformations for the A5/RSK1 complex. Ligands A5, A6, A10, A12, A17, A11, A4, and A13, featuring diverse functional groups and good Glide scores, may have the potential for significant RSK1 activity and merit further development.Communicated by Ramaswamy H. Sarma.

Functional group modifications at the 8-position of Manzamine A enhance its inhibitory activity against RSK1.Amine and carbonyl groups at position 8 of Manzamine A enhance its inhibitory activity, especially when accompanied by an aryl group.This research lays a solid groundwork for future drug development targeting RSK1, offering promising candidates for further investigation.

Anti-enzymatic and DNA docking studies of montelukast: A multifaceted molecular scaffold with in vitro investigations, molecular expression analysis and molecular dynamics simulations.

Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the present studies, montelukast was subjected to in vitro inhibitory assays followed by kinetic and in silico investigations. Montelukast demonstrated inhibitory activity against yeast α-glucosidase (IC50 44.31 ± 1.21 µM), jack bean urease (JB urease, IC50 8.72 ± 0.23 µM), human placental alkaline phosphatase (hPAP, IC50 17.53 ± 0.19 µM), bovine intestinal alkaline phosphatase (bIAP, IC50 15.18 ± 0.23 µM) and soybean 15-lipoxygenase (15-LOX, IC50 2.41 ± 0.13 µM). Kinetic studies against α-glucosidase and urease enzymes revealed its competitive mode of inhibition. Molecular expression analysis of montelukast in breast cancer cell line MCF-7 down-regulated AP by a factor of 0.27 (5 µM) compared with the 0.26 value for standard inhibitor levamisole (10 µM). Molecular docking estimated a binding affinity ranging -8.82 to -15.65 kcal/mol for the enzymes. Docking against the DNA dodecamer (ID: 1BNA) observed -9.13 kcal/mol via minor groove binding. MD simulations suggested stable binding between montelukast and the target proteins predicting strong inhibitory potential of the ligand. Montelukast features a chloroquinoline, phenyl ring, a cyclopropane group, a carboxylic group and a sulfur atom all of which collectively enhance its inhibitory potential against the said enzymes. These in vitro and computational investigations demonstrate that it is possible and suggested that the interactions of montelukast with more than one targets presented herein may be linked with the side effects presented by this drug and necessitate additional work. The results altogether suggest montelukast as an important structural scaffold possessing multitargeted features and warrant further investigations in repurposing beyond its traditional pharmacological use.

3D-QSAR pharmacophore modeling, virtual screening, molecular docking, MD simulations, in vitro and in vivo studies to identify potential anti-hyperplasia drugs.

Psoriasis is a common immune-mediated skin condition characterized by aberrant keratinocytes and cell proliferation. The purpose of this study was to explore the FDA-approved drugs by 3D-QSAR pharmacophore model and evaluate their efficiency by in-silico, in vitro, and in vivo psoriasis animal model. A 3D-QSAR pharmacophore model was developed by utilizing HypoGen algorithm using the structural features of 48 diaryl derivatives with diverse molecular patterns. The model was validated by a test set of 27 compounds, by cost analysis method, and Fischer's randomization test. The correlation coefficient of the best model (Hypo2) was 0.9601 for the training set while it was 0.805 for the test set. The selected model was taken as a 3D query for the virtual screening of over 3000 FDA-approved drugs. Compounds mapped with the pharmacophore model were further screened through molecular docking. The hits that showed the best docking results were screened through in silico skin toxicity approach. Top five hits were selected for the MD simulation studies. Based on MD simulations results, the best two hit molecules, that is, ebastine (Ebs) and mebeverine (Mbv) were selected for in vitro and in vivo antioxidant studies performed in mice. TNF-α and COX pro-inflammatory mediators, biochemical assays, histopathological analyses, and immunohistochemistry observations confirmed the anti-inflammatory response of the selected drugs. Based on these findings, it appeared that Ebs can effectively treat psoriasis-like skin lesions and down-regulate inflammatory responses which was consistent with docking predictions and could potentially be employed for further research on inflammation-related skin illnesses such as psoriasis.

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies.

Considerable ingenuity has been shown in the recent years in the discovery of novel xanthine oxidase (XO) inhibitors that fall outside the purine scaffold. The triazole nucleus has been the cornerstone for the development of many enzyme inhibitors for the clinical management of several diseases, where hyperuricemia is one of them. Here, we give a critical overview of significant research on triazole-based XO inhibitors, with respect to their design, synthesis, inhibition potential, toxicity, and docking studies, done till now. Based on these literature findings, we can expect a burst of modifications on triazole-based scaffolds in the near future by targeting XO, which will treat hyperuricemics, that is, painful conditions like gout that at present are hard to deal with.

Novel N-(3-ethynyl Phenyl)-6,7-bis(2-methoxyethoxy)Quinazoline-4-amine Derivatives: Synthesis, Characterization, Anti-cancer Activity, In-silico and DFT Studies.

BACKGROUND: Cancer is one of the most common reasons for mortality in the world. A continuous effort to develop effective anti-cancer drugs with minimum side effects has become necessary. The use of small-molecule drugs has revolutionized cancer research by inhibiting cancer cell survival and proliferation. Quinazolines are a class of bioactive heterocyclic compounds with active pharmacophores in several anti-cancer drugs. Such small molecule inhibitors obstruct the significant signals responsible for cancer cell development, thus blocking these cell signals to prevent cancer development and spread. OBJECTIVE: In the current study, novel quinazoline derivatives structurally similar to erlotinib were synthesized and explored as novel anti-cancer agents. METHODS: All the synthesized molecules were confirmed by spectroscopic techniques like 1H NMR, 13C NMR, and ESI-MS. Various techniques were applied to study the protein-drug interaction, DFT analysis, Hirshfeld surface, and target prediction. The molecules were screened in vitro for their anti-cancer properties against 60 human tumor cell lines. The growth inhibitory properties of a few compounds were studied against the MCF7 breast cancer cell line. RESULTS: The activity of compounds 9f, 9o, and 9s were found to be active. However, compound 9f is more active when compared with other compounds. CONCLUSION: Some synthesized compounds were active against different cancer cell lines. The in-vitro study results were found to be in agreement with the predictions from in-silico data. The selected molecules were further subjected to get the possible mechanism of action against different cancer cells.

Cytotoxicity Activity of Some meso-Dihydroguaiaretic Acid Derivatives and Mode of Action of the Most Active Compound.

The aim of this study was to screen sixteen meso-1 semi-synthetic derivatives bearing ether, esther, carbamate, phosphate or aminoether functional groups against five cancer cell lines: MCF-7 (breast), A549 (lung), HepG2 (liver), HeLa (cervix), and DU145 (prostate) at 25 µM using the MTT assay. Results from the screening showed that two derivatives had the lowest percentage of cell viability at 25 µM, the aminoether derivative meso-11 and the esther derivative meso-20 against A549 (44.15±0.78 %) and MCF-7 (41.60±0.92 %), respectively. Then, it was determined the IC50 value of each compound against their most sensitive cancer cell line. Results showed that aminoether derivative meso-11 showed potent cytotoxicity against A549 (IC50 =17.11±2.11 µM), whereas it resulted more cytotoxic against the LL-47 lung normal cell line (IC50 =9.49±1.19 µM) having a Selective Index (SI) of 0.55. On the other hand, the esther derivative meso-20 exhibited potent activity against MCF-7 (IC50 =18.20±1.98 µM), whereas it displayed moderate cytotoxicity against the MCF-10 breast normal cell line (IC50 =41.22±2.17 µM) with a SI of 2.2. Finally, studies on the mechanism of action of meso-20 indicated disruption of MCF-7 plasma membrane in vitro and the AMPK activation in silico.