Computational Chemistry: Prediction of Compound Accessibility of Targeted Synthesized Compounds.

INTRODUCTION: In the present work, a series of novel pyridine carboxamides 3(a-h) were synthesized and screened with antibacterial activity. This research explores the application of Density Functional Theory (DFT) in studying biological systems at the quantum mechanical level, particularly in the context of drug design. DFT offers a streamlined approach to quantum mechanical calculations, making it indispensable in various scientific fields, and for its exceptional accuracy, reduced computational time, and cost-effectiveness has become a pivotal tool in computational chemistry. This research work highlights the integration of DFT studies with POM analyses, which effectively identify pharmacophoric sites. Moreover, the research incorporates in silico pharmacokinetics analyses to assess the pharmacokinetic properties of synthesized compounds. The paper focused on a series of compounds previously reported, aiming to provide a comprehensive understanding of their electronic structure, pharmacophoric features, and potential as drug candidates. This study not only contributes to the evolving field of computational chemistry but also holds implications for advancing drug design processes by combining theoretical insights with practical analyses. METHODS: The compounds 3(a-h) were subjected to Density Functional Theory (DFT) computations using the B3LYP/6-31G(d) basis set to get optimized geometric structures. GaussViewis used to display the contributions of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The determination of energy gaps was conducted using Gaussian 09W. The pharmacokinetic profiles were evaluated using existing techniques such as Osiris, Petra, and Molinspiration, as well as a novel platform called POM Analyse. RESULTS: The computational studies DFT, POM and in silico pharmacokinetics studies revealed that the studied compounds are biologically active, non-toxic, non-carcinogenic in nature and may be utilized as drug candidates. CONCLUSION: Density functional theory (DFT) investigations emphasize the exceptional stability of complex 3d, which possesses the biggest energy gap and the lowest softness. In contrast, compound 3h demonstrates poorer stability among the tested compounds, characterized by the lowest energy gap and the highest softness values. These findings are further substantiated by absolute energy calculations. The negligible energy difference in compound 3h indicates an increased transfer of electric charge within the molecule, which is associated with its enhanced biological effectiveness. The drug-likeness of the compounds is confirmed by POM and in silico pharmacokinetics investigations, with compound 3h being identified as the most biologically active among the investigated compounds.

In vitro and in vivo evaluation of the antimicrobial, antioxidant, cytotoxic, hemolytic activities and in silico POM/DFT/DNA-binding and pharmacokinetic analyses of new sulfonamide bearing thiazolidin-4-ones.

In this work, Schiff bases and Thiazolidin-4-ones, were synthesized using Sonication and Microwave techniques, respectively. The Schiff base derivatives (3a-b) were synthesized via the reaction of Sulfathiazole (1) with benzaldehyde derivatives (2a-b), followed by the synthesis of 4-thiazoledinone (4a-b) derivatives by cyclizing the synthesized Schiff bases through thioglycholic acid. All the synthesized compounds were characterized by spectroscopic techniques such as FT IR, NMR and HRMS. The synthesized compounds were tested for their in vitro antimicrobial and antioxidant and in vivo cytotoxicity and hemolysis ability. The synthesized compounds displayed better antimicrobial and antioxidant activity and low toxicity in comparison to reference drugs and negative controls, respectively. The hemolysis test revealed the compounds exhibit lower hemolytic effects and hemolytic values are comparatively low and the safety of compounds is in comparison with standard drugs. Theoretical calculations were carried out by using the molecular operating environment (MOE) and Gaussian computing software and observations were in good agreement with the in vitro and in vivo biological activities. Petra/Osiris/Molinspiration (POM) results indicate the presence of three combined antibacterial, antiviral and antitumor pharmacophore sites. The molecular docking revealed the significant binding affinities and non-bonding interactions between the compounds and Erwinia Chrysanthemi (PDB ID: 1SHK). The molecular dynamics simulation under in silico physiological conditions revealed a stable conformation and binding pattern in a stimulating environment. HighlightsNew series of Thaiazolidin-4-one derivatives have been synthesized.Sonication and microwave techniques are used.Antimicrobial, Antioxidant, cytotoxicity, and hemolysis activities were observed for all synthesized compounds.Molecular Docking and DFT/POM analyses have been predicted.Communicated by Ramaswamy H. Sarma.

Sustainable and Green Corrosion Inhibition of Mild Steel: Insights from Electrochemical and Computational Approaches.

Natural and fragrant compounds, essential oils (EOs) extracted from plants through hydrodistillation, are gaining popularity as eco-friendly and sustainable agents to protect metals and alloys from corrosion in acidic environments. This research focused on extracting and characterizing an EO obtained from the Cuminum cyminum (CC) plant native to India. The study aimed to evaluate the inhibitory properties of this EO on mild steel in a 0.5 M HCl solution at different concentrations. Various analytical techniques, including potentiodynamic polarization curves, electrochemical impedance spectroscopy, optical microscopy, infrared spectroscopy, and proton magnetic resonance, were employed to assess the effectiveness of this EO extract. Our findings indicate that the Cuminum cyminum L (CCL) extract effectively reduces the corrosion of mild steel in hydrochloric acid with an inhibition efficiency ranging from 79.69 to 98.76%. The optimal inhibition concentration was 2 g/L of EO, and surface analysis confirmed the formation of a protective layer. Furthermore, our results suggest that the inhibitor binds to the metal surface through a charge-transfer process, creating a protective film. Finally, we utilized theoretical calculations and molecular dynamics simulations to elucidate the inhibition mechanism on both a global and local scale.

Novel N-acylsulfonamides: Synthesis, in silico prediction, molecular docking dynamic simulation, antimicrobial and anti-inflammatory activities.

Microbial resistance to drugs currently traded in the market is a serious problem in modern medicine. In this field of research, we synthesized a novel N-acylsulfonamides (NAS) derivatives starting from commercially available compounds; morpholine, isocyanate of chlorosulfonyl and alcohols. The in vitro antimicrobial potential of synthesized compounds was screened against 04 Gram-negative bacteria; Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, 02 Gram-positive bacteria: Streptococcus sp, Staphylococcus aureus and 07 yeasts and fungi: Candida albicans, Candida spp, Penicillum spp, Aspegillus sp, Aspergillus flavus, Fusarium sp, and Cladosporium spp. The results of inhibition growth were compared with standard antimicrobial drugs with the goal of exploring their potential antimicrobial activity. In addition, the anti-inflammatory activity of the synthesized compounds was determined in-vitro by protein denaturation method. The obtained bioactivity results were further validated by in silico DFT (Density Functional Theory), ADME (Absorption-Distribution-Métabolisation-Excrétion), molecular docking studies and molecular dynamics simulations.Communicated by Ramaswamy H. Sarma.

Green synthesis, antibacterial and antifungal evaluation of new thiazolidine-2,4-dione derivatives: molecular dynamic simulation, POM study and identification of antitumor pharmacophore sites.

In this study, a series of thiazolidine-2,4-dione derivatives 3a-i were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative strains of Bacillus licheniformis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Newly prepared thiazolidine (TZD) derivatives were further screened separately for in vitro antifungal activity against cultures of fungal species, namely, Aspergillus niger, Alternaria brassicicola, Chaetomium murorum, Fusarium oxysporum, Lycopodium sp. and Penicillium notatum. The electron-donating substituents (-OH and -OCH3) and electron-withdrawing substituents (-Cl and -NO2) on the attached arylidene moieties of five-membered heterocyclic ring enhanced the broad spectrum of antimicrobial and antifungal activities. The molecular docking study has revealed that compound 3h strongly interacts with the catalytic residues of the active site of the ß-carbonic anhydrase (P. aeruginosa) and has the best docking score. In silico pharmacokinetics studies showed the drug-likeness and non-toxic nature of the synthesized compounds, which indicates the combined antibacterial, antiviral and antitumor pharmacophore sites of the targeted drug. This work demonstrates that potential TZD derivatives bind to different types of bacterial and fungal pathogens for circumventing their activities and opens avenues for the development of newer drug candidates that can target bacterial and fungal pathogens.Communicated by Ramaswamy H. Sarma.

Antibacterial, Cytotoxic and Genotoxic Assessment of New Sulfonamide Derivatives.

In the last few years, the interest in sulfonamides has expanded owing to their broad spectrum of biological activities. Their flexible structure turns them into amazing candidates to replace old drugs or develop modern multi-target agents. In this study, a series of new sulfonamides (sul1-5) was evaluated, in vitro, for the antibacterial, cytotoxic and genotoxic effects. The antibacterial activity was investigated against 12 clinical and 4 reference strains. Cytotoxic activity was carried out by the brine shrimp bioassay and the genotoxicity was assessed in the Ames test. An interesting antibacterial activity was showed especially against Gram negative strains. The inhibition zones varied between 15 and 30 mm, and the Minimum Inhibitory Concentrations (MIC's) values between 0.5 and 256 µg/ml. No antibacterial activity was shown with S. aureus isolates. Only Sul1 and Sul4 were active against P. aeruginosa. Compounds Sul1 and Sul2 showed a significant cytotoxicity with LC50 equal to 18.29 and 18 µg/ml respectively, and a genotoxic effect against TA100 and TA1535 Salmonella strains. Only compounds Sul3, Sul4 and Sul5 with an interesting antibacterial activity, no cytotoxicity and no genotoxic effects, could be exploited against resistant pathogens as new drugs.

Theoretical, antioxidant, antidiabetic and in silico molecular docking and pharmacokinetics studies of heteroleptic oxovanadium(IV) complexes of thiosemicarbazone-based ligands and diclofenac.

A series of new heteroleptic oxovanadium(IV) complexes with the general formula [VOL1-6(Dcf)] (1-6), where L1-6 = thiosemicarbazone (TSC)-based ligands and Dcf = diclofenac have been synthesized and characterized. The spectral studies along with the density functional theory calculations evidenced the distorted square-pyramidal geometry around oxovanadium(IV) ion through imine nitrogen and thione sulfur atoms of TSC moiety, and two asymmetric carboxylate oxygen atoms of diclofenac drug. The complexes were evaluated for in vitro antioxidant activity using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and superoxide radical scavenging assays with respect to the standard antioxidant drugs butylated hydroxyanisole (BHA) and rutin. The in vitro antidiabetic activity of the complexes was tested with enzymes such as α-amylase, α-glucosidase and glucose-6-phosphatase. The complexes containing methyl substituent showed higher activity than that containing the nitro substituent due to the electron-donating effect of methyl group. The in silico molecular docking studies of the oxovanadium(IV) complexes with α-amylase and α-glucosidase enzymes showed strong interaction via hydrogen bonding and hydrophobic interactions. The dynamic behavior of the proposed complexes was analyzed by molecular dynamics (MDs) simulations, which revealed the stability of docked structures with α-amylase and α-glucosidase enzymes. The in silico physicochemical and pharmacokinetics parameters, such as Lipinski's 'rule of five', Veber's rule and absorption, distribution, metabolism and excretion (ADME) properties predicted non-toxic, non-carcinogenic and safe oral administration of the synthesized complexes.Communicated by Ramaswamy H. Sarma.

Anticancer activity, DFT study, ADMET prediction, and molecular docking of novel α-sulfamidophosphonates.

A series of novel α-sulfamidophosphonate derivatives (3a-3 g) were synthesized and evaluated for anticancer activity against different human cancer cell lines (PRI, K562, and JURKAT). The antitumor activity of all compounds using the MTT test remains moderate compared to the standard drug chlorambucil. Compounds 3c and 3 g were found to be more active anticancer agent against PRI and K562 cells with IC50 value 0.056-0.097 and 0.182-0.133 mM, respectively. Molecular docking study related to binding affinity and binding mode analysis showed that synthesized compounds had potential to inhibit glutamate carboxypeptidase II (GCPII). Furthermore, computational analysis was performed through Density Functional Theory (DFT) utilizing the B3LYP 6-31 G (d, p) basis set and the theoretical results were correlated with experimental data. The ADME/toxicity analyses carried out by Swiss ADME and OSIRIS software show that all synthesized molecules exhibited good pharmacokinetics, bioavailability, and had no toxicity profile.

In silico evaluation of molecular interactions between macrocyclic inhibitors with the HCV NS3 protease. Docking and identification of antiviral pharmacophore site.

An array of computational approaches DFT/QSAR/POM methods has been used for a better understanding of drug properties regarding 13 inhibitor derivatives containing either P2 cyclopentane P1 carboxylic acid moiety (1-9) or a P1 cyclopropyl acyl sulfonamide (10-13). To further recognize binding interactions and their activity trends, molecular docking studies were carried out with the use of HCV, which can be used to accurately predict the interactions of ligands with the receptor. The QSAR models are developed through the use of Multiple Linear Regression (MLR) together with Principal Component Analysis (PCA) methods. The statistical results indicate the multiple correlation coefficient R2 = 0.840, which shows favorable estimation stability, as well as showing a significant correlation between the HCV NS3 protease of the studied compounds and their electron-accepting ability. The POM analysis of the Physico-chemical properties of compounds 1-13, shows that they are bearing (O1, O2) and/or (O1, O2, O3) antiviral pockets, whereby all oxygen atoms are Osp2 and bearing negative charges. Similar to the reference ligand (F9K), the most active compound 10 was bound deeply into the binding cavity of NS3 protease making interactions with the residues Gly137, His57, Ala157, and His528. The anti-hepatitis pharmacophore site is similar to the anti-HIV pharmacophore site.Communicated by Ramaswamy H. Sarma.

Efficient synthesis and antitumor activity of novel oxazaphosphinane derivatives: X-ray crystallography, DFT study and molecular docking.

A novel potentially biologically active oxazaphosphinane derivatives was synthesized by facile synthetic approaches from the combination of hydroxyaniline, aldehyde, and triethylphosphite. The crystal structure of compound 1b has been determined. Single crystals belong to the triclinic system with p - 1 space. The relative in vitro antitumor activity against human cell lines (PRI, K562, and JURKAT) of these derivatives in comparison to chlorombucil is reported. All synthesized compound showed excellent activity with IC50 value of 0.014-0.035 mM. The binding energy of the Epidermal growth factor receptor (EGFR)-oxazaphosphinane complex and the calculated inhibition constant using docking simulation showed that all molecules has the ability to inhibit EGFR therapeutic target. In addition, DFT calculation has been used to analyze the electronic and geometric characteristics.Communicated by Ramaswamy H. Sarma.

Experimental and theoretical insights into copper corrosion inhibition by protonated amino-acids.

The effects of cysteine (Cys) and l-methionine (l-Met) on copper corrosion inhibition were examined in 1 M HNO3 solution for short and long exposure times. Potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) were used. The EIS determined the potential for zero charges of copper (PZC) in the inhibitor solution. SEM and AFM have been used to study material surfaces. Energy-dispersive X-ray spectroscopy (EDS) was used to identify surface elemental composition. DFT and molecular dynamics simulations explored the interaction between protonated amino acids and aggressive media anions on a copper (111) surface.

Crystallographic study, biological assessment and POM/Docking studies of pyrazoles-sulfonamide hybrids (PSH): Identification of a combined Antibacterial/Antiviral pharmacophore sites leading to in-silico screening the anti-Covid-19 activity.

The discovery and development of new potent antimicrobial and antioxidant agents is an essential lever to protect living beings against pathogenic microorganisms and free radicals. In this regard, new functionalized pyrazoles have been synthesized using a simple and accessible approach. The synthesized aminobenzoylpyrazoles 3a-h and pyrazole-sulfonamides 4a-g were obtained in good yields and were evaluated in vitro for their antimicrobial and antioxidant activities. The structures of the synthesized compounds were determined using IR, NMR, and mass spectrometry. The structure of the compound 4b was further confirmed by single crystal X-ray diffraction. The results of the in vitro screening show that the synthesized pyrazoles 3 and 4 exhibit a promising antimicrobial and antioxidant activities. Among the tested compounds, pyrazoles 3a, 3f, 4e, 4f, and 4g have exhibited remarkable antimicrobial activity against some microorganisms. In addition, compounds 3a, 3c, 3e, 4a, 4d, 4f, and 4g have shown a significant antioxidant activity in comparison with the standard butylhydroxytoluene (BHT). Hence, compounds 3a, 4f, and 4g represent interesting dual acting antimicrobial and antioxidant agents. In fact, pyrazole derivatives bearing sulfonamide moiety (4a-g) have displayed an important antimicrobial activity compared to pyrazoles 3a-h, this finding could be attributed to the synergistic effect of the pyrazole and sulfonamide pharmacophores. Furthermore, Molecular docking results revealed a good interaction of the synthesized compounds with the target proteins and provided important information about their interaction modes with the target enzyme. The results of the POM bioinformatics investigations (Petra, Osiris, Molinspiration) show that the studied heterocycles present a very good non toxicity profile, an excellent bioavailability, and pharmacokinetics. Finally, an antiviral pharmacophore (O δ-, O δ-) was evaluated in the POM investigations and deserves all our attention to be tested against Covid-19 and its Omicron and Delta mutants.

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations.

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC50 values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC50 values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski's rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.

Synthesis, in silico study (DFT, ADMET) and crystal structure of novel sulfamoyloxy-oxazolidinones: Interaction with SARS-CoV-2.

A new series of sulfamoyloxyoxazolidinone (SOO) derivatives have been synthesized and characterized by single-crystal X-ray diffraction, NMR, IR, MS and EA. Chemical reactivity and geometrical characteristics of the target compounds were investigated using DFT method. The possible binding mode between SOO and Main protease (Mpro) of SARS-CoV-2 and their reactivity were studied using molecular docking simulation. Single crystal X-ray diffraction showed that SOO crystallizes in a monoclinic system with P 2 1 space group. The binding energy of the SARS-CoV-2/Mpro-SOO complex and the calculated inhibition constant using docking simulation showed that the active SOO molecule has the ability to inhibit SARS-CoV2. We studied the prediction of absorption, distribution, properties of metabolism, excretion and toxicity (ADMET) of the synthesized molecules.

How to face COVID-19: proposed treatments based on remdesivir and hydroxychloroquine in the presence of zinc sulfate. Docking/DFT/POM structural analysis.

Remdesivir and hydroxychloroquine derivatives form two important classes of heterocyclic compounds. They are known for their anti-malarial biological activity. This research aims to analyze the physicochemical properties of remdesivir and hydroxychloroquine compounds by the computational approach. DFT, docking, and POM analyses also identify antiviral pharmacophore sites of both compounds. The antiviral activity of hydroxychloroquine compound's in the presence of zinc sulfate and azithromycin is evaluated through its capacity to coordinate transition metals (M = Cu, Ni, Zn, Co, Ru, Pt). The obtained bioinformatic results showed the potent antiviral/antibacterial activity of the prepared mixture (Hydroxychloroquine/Azithromycin/Zinc sulfate) for all the opportunistic Gram-positive, Gram-negative in the presence of coronavirus compared with the complexes Polypyridine-Ruthenium-di-aquo. The postulated zinc(II) complex of hydroxychloroquine derivatives are indeed an effective antibacterial and antiviral agent against coronavirus and should be extended to other pathogens. The combination of a pharmacophore site with a redox [Metal(OH2)2] moiety is of crucial role to fight against viruses and bacteria strains. [Formula: see text]Communicated by Ramaswamy H. Sarma.

Mechanistic basis of breast cancer resistance protein inhibition by new indeno[1,2-b]indoles.

The ATP-binding cassette transporter ABCG2 mediates the efflux of several chemotherapeutic drugs, contributing to the development of multidrug resistance (MDR) in many cancers. The most promising strategy to overcome ABCG2-mediated MDR is the use of specific inhibitors. Despite many efforts, the identification of new potent and specific ABCG2 inhibitors remains urgent. In this study, a structural optimization of indeno[1,2-b]indole was performed and a new generation of 18 compounds was synthesized and tested as ABCG2 inhibitors. Most compounds showed ABCG2 inhibition with IC50 values below 0.5 µM. The ratio between cytotoxicity (IG50) and ABCG2 inhibition potency (IC50) was used to identify the best inhibitors. In addition, it was observed that some indeno[1,2-b]indole derivatives produced complete inhibition, while others only partially inhibited the transport function of ABCG2. All indeno[1,2-b]indole derivatives are not transported by ABCG2, and even the partial inhibitors are able to fully chemosensitize cancer cells overexpressing ABCG2. The high affinity of these indeno[1,2-b]indole derivatives was confirmed by the strong stimulatory effect on ABCG2 ATPase activity. These compounds did not affect the binding of conformation-sensitive antibody 5D3 binding, but stabilized the protein structure, as revealed by the thermostabilization assay. Finally, a docking study showed the indeno[1,2-b]indole derivatives share the same binding site as the substrate estrone-3-sulfate.

Ninhydrins inhibit carbonic anhydrases directly binding to the metal ion.

Ninhydrins show extensive application in organic chemistry and agriculture whereas they have been poorly investigated as bioactive molecules for medicinal chemistry purposes. A series of ninhydrin derivatives was here investigated for the inhibition of human carbonic anhydrases (CAs, EC 4.2.1.1), based on earlier evidence that gem diols are able to coordinate the metal ion from the CA active site. Ninhydrins demonstrated a micromolar inhibitory action against CA I and IX (KIs in the range 0.57-68.2 µM) and up to a nanomolar efficacy against CA II and VII (KIs in the range 0.025-78.2 µM), validated isoforms as targets in several CNS-related diseases. CA IV was instead weakly or poorly inhibited. A computational protocol based on docking, MM-GBSA and metadynamics calculations was used to elucidate the putative binding mode of this type of inhibitors to CA II and CA VII. The findings of this study testify that such pharmacologically underestimated ligands may represent interesting lead compounds for the development of CA inhibitors possessing an innovative mechanism of action, i.e., mono- or bis-coordination to the zinc ion through the diol moiety.

Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2.

Multidrug resistance membrane pumps reduce the efficacy of chemotherapies by exporting a wide panel of structurally-divergent drugs. Here, to take advantage of the polyspecificity of the human Breast Cancer Resistance Protein (BCRP/ABCG2) and the dimeric nature of this pump, new dimeric indenoindole-based inhibitors from the monomeric α,ß-unsaturated ketone 4b and phenolic derivative 5a were designed. A library of 18 homo/hetero-dimers was synthesised. Homo-dimerization shifted the inhibition efficacy from sub-micromolar to nanomolar range, correlated with the presence of 5a, linked by a 2-6 methylene-long linker. Non-toxic, the best dimers displayed a therapeutic ratio as high as 70,000. It has been found that the high potency of the best compound 7b that displays a KI of 17 nM is due to an uncompetitive behavior toward mitoxantrone efflux and specific for that drug, compared to Hoechst 33342 efflux. Such property may be useful to target such anticancer drug efflux mediated by ABCG2. Finally, at a molecular level, an uncompetitive mechanism by which substrate promotes inhibitor binding implies that at least 2 ligands should bind simultaneously to the drug-binding pocket of ABCG2.

Medicinal Applications of Cannabinoids Extracted from Cannabis sativa (L.): A New Route in the Fight Against COVID-19?

Cannabis sativa is a well-known plant that has been recognized for its benefits since ancient times by several medicinal systems, including those of China, India, Greece, and Egypt. Although C. sativa is one of the most investigated medicinal plants in the world, it faces some of the greatest controversies surrounding its legalization and use as a medication. C. sativa contains several hundred phytoconstituents, including the infamous "cannabinoids". It is necessary to properly understand the medicinal importance of these phytochemicals and spread awareness among the countries where cannabis is still facing legal obstacles. The current review focuses on the most recent literature pertaining to various applications of cannabinoids, with a special focus on the medicinal aspect of these phytochemicals. Peer-reviewed articles focusing on the importance of cannabis and cannabinoids are the target of this review. Articles were selected based on the relevance to the general scope of the work, i.e., application of cannabinoids. Cannabinoids can truly be regarded as wonder drugs, considering their immense diversity of usage. Unfortunately, however, many of the mares have never been researched biologically or pharmacologically due to their low yield in the plant. However, the approval of some cannabinoids by the FDA (along with other recognized national medical health systems) has opened the horizon for the use of these natural drugs in medicines such as Epidiolex® (cannabidiol, used for the treatment of severe forms of epilepsy) and Sativex®(Δ9-tetrahydrocannabinol and cannabidiol, used for the treatment of spasticity caused by multiple sclerosis). Many pharmacological properties of C. sativa are attributed to cannabidiol (CBD), a non-psychoactive component, along with Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive component. This review addresses the most important applications or current utilization of cannabinoids in a variety of treatments such as chronic pain, cancer, emesis, anorexia, irritable bowel syndrome, communicable diseases, glaucoma, and central nervous system disorders. The biosynthetic pathway of cannabinoids is also discussed. In short, cannabis has a myriad of bioactive compounds that have the potential to increase the list of approved cannabinoids suitable for therapy.

Synthesis, biological activity and POM/DFT/docking analyses of annulated pyrano[2,3-d]pyrimidine derivatives: Identification of antibacterial and antitumor pharmacophore sites.

New annulated pyrano[2,3-d]pyrimidine derivatives were synthesized with hydroxyl, methoxy, bromine, nitrile and nitro substituents on its skeleton. The correlated electronic effect of substituents on the magnitude of antibacterial activity was noted. The electron donating substituents (namely; 4-OH, 4-OCH3, 4-Br) and electron withdrawing substituents (4-NO2) on phenyl ring in the pyrano[2,3-d]pyrimidine skeleton exerted different influence on its antimicrobial activity against some Gram-positive and Gram-negative bacteria such as Pseudomonas aureus, E. coli, Staphylococcus aureus, Klebsiella pneumonia and Bacillus cereus. All the pyrano[2,3-d]pyrimidines were characterized by spectroscopic analyses. Antibacterial screening revealed that the presence of heteroaryl, cyano and amino groups on pyrano[2,3-d]pyrimidine skeleton increases its penetrating power on the bacterial cell wall so that the product becomes more biologically active. So the the nature of electron withdrawing or electro-donnor Impact of substituents should be taken in consideration in drug design. Hydrolysis of -CRN to amide restored vital Intramolecular interaction like ortho-nitrophenyl and ONOδ-…NHδ+/amide link, offering a crucial template for antibacterial NH, HO-pharmacophore sites, which ultimately elevated innate antimicrobial profiles. POM combinatorial analysis of tangible electronic contributions due to armed annulated pyrano[2,3-d]pyrimidines concluded their broad antimicrobial activity and viable/prominent drug score index through perspective parameters particularly: inter atomic distance/linkers, steric, electronic, polar parameters, and with a different polarising effect of electron donating/withdrawing environments of substituents. Furthermore, an anti-Kinase pharmacophore site (OCNHCO) was evaluated in continuation of the POM investigations. All synthesized products verified fewer side effects than standard streptomycin, but facile implication in selective cancer media (viz. breast or leucemia still needs to be screened).