Naphtho[2,1-b]furan derived triazole-pyrimidines as highly potential InhA and Cytochrome c peroxidase inhibitors: Synthesis, DFT calculations, drug-likeness profile, molecular docking and dynamic studies

Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 6(a-f). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using B3LYP hybrid functional with a 6–31+G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK),Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6ahad excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified. © 2023

Synthesis, structural characterization, thermal analysis, DFT, biocidal evaluation and molecular docking studies of amide-based Co(II) complexes.

Abstract: Many distinct amino acid and aromatic amine-derived transition metal complexes are used as physiologically active compounds. A few Cobalt (II) complexes have been synthesized by reacting cobalt (II) chloride with 1, 8-diaminonapthalene-based tetraamide macrocyclic ligands in an ethanolic media. These synthesized ligands (TAML1-3) and associated Co(II) complexes were fully characterized with various spectroscopic techniques, such as IR, NMR, CHN analysis, EPR, molar conductance, and magnetic susceptibility measurements, TGA, UV-visible spectra, powder X-ray diffraction and DFT analysis. The IR spectra reveal interactions between the core metal atom and ligands through N of 1, 8-diaminonapthalene. The distorted octahedral geometry of synthesized Co(II) macrocyclic complexes were confirmed by ESR, UV-Vis and DFT studies. The synthesized ligands (TAML1-TAML3) and their Co(II) complexes were tested for antimicrobial activity against A. niger, C. albicans, and F. oxysporum in addition to bacteria like S. aureus, B. subtilis, and Gram-negative bacteria like E. coli. The ligand TAML1 and complex [Co(TAML1)Cl2] showed an excellent antibacterial activity. The minimum inhibitory concentration of TAML1 and [Co(TAML1)Cl2] against S. aureus were found to be 7 mm and 10 mm zone of inhibition at 500 ppm, respectively, compared to drug ampicillin (3 mm). Additionally, each molecule exhibited notable antioxidant activity. The biological significance of the synthesized compounds was then evaluated by molecular docking experiments with the active site of the receptor protein such as Sars-Cov-2, C. Albicans, X. campestris and E. coli. The molecular docking assisted data strongly correlated to the experimental approach of antimicrobial activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-023-02843-y.

Synthesis, antitubercular evaluation, and molecular docking studies of hybrid pyridinium salts derived from isoniazid.

In the quest to develop potent inhibitors for Mycobacterium tuberculosis, novel isoniazid-based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities against the H37 Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l, and 7d showed exceptional antimycobacterial activities with MIC90 at 1 µg/mL. The in vitro cytotoxicity and pharmacokinetics profiles of these compounds were established for the identification of a lead molecule using in vivo efficacy proof-of-concept studies and found that the lead compound 4k possesses LC50 value at 25 µg/mL. The in vitro antimycobacterial activity results were further supported by in silico studies with good binding affinities ranging from -9.8 to -11.6 kcal/mol for 4k, 4l, and 7d with the target oxidoreductase DprE1 enzyme. These results demonstrate that pyridinium salts derived from isoniazid can be a potentially promising pharmacophore for the development of novel antitubercular candidates.

New 6'-Amino-5'-cyano-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-pyridine]-3'-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity.

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6'-amino-3'-(aminocarbonyl)-5'-cyano-2-oxo-1,2-dihydro-1'H- and 6'-amino-3'-(aminocarbonyl)- 5'-cyano-2-oxo-1,2-dihydro-3'H-spiro[indole-3,4'-pyridine]-2'-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4'-pyridine]-2'-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6'-amino-5'-cyano-5-methyl-2-oxo-2'-thioxo-1,2,2',3'-tetrahydro-1'H-spiro-[indole-3,4'-pyridine]- 3'-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4'-pyridine]-2'-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2'-amino-6'-[(2-aryl-2-oxoethyl)thio]-3'-cyano-2-oxo-1'H-spiro[indoline-3,4'-pyridine]-5'-carboxamides and 5'-amino-3'-aryl-6'-cyano-3'-hydroxy-2-oxo-2',3'-dihydrospiro[indoline-3,7'-thiazolo[3,2-a]pyridine]-8'-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of -5.8 to -8.2 kcal/mol. In addition, one of the new compounds, 2'-amino-3'-cyano-5-methyl-2-oxo-6'-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1'H-spiro-[indoline-3,4'-pyridine]-5'-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.

Activity of Some Novel Chalcone Substituted 9-anilinoacridines against Coronavirus (COVID-19): A Computational Approach

Background: In the year earlier part of 2020, many scientists urged to discover novel drugs against for the treatments of COVID-19. Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease, was discovered first in China and quickly spread throughout the world. Objective(s): In the present article, some novel chalcone substituted 9-anilinoacridines (1a-z) were developed by in silico studies for their COVID19 inhibitory activity. Molecular docking studies of the ligands 1a-z were performed against COVID19 (PDB id-5R82) targeting the coronavirus using Schrodinger suite 2019-4. Method(s): The molecular docking studies were performed by the Glide module and the binding energy of ligands was calculated using the PRIME MM-GB/SA module of Schrodinger suite 2019-4. Result(s): From the results, many compounds are significantly active against COVID19 with a Glide score of more than-5.6 when compared to the currently used drug for the treatment of COVID19, Hy-droxychloroquine (-5.47). The docking results of the compounds exhibited similar mode of interactions with COVID19 and the residues, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, VAL186, HIE164, ASN142, and GLY143 play a crucial role in binding with ligands. MM-GBSA binding calculations of the most potent inhibitors are more stably favourable. Conclusion(s): From the results of in-silico studies, it provides strong evidence for the consideration of valuable ligands in chalcone substituted 9-anilinoacridines as potential COVID19 inhibitors and the compounds, 1x,a,r,s with significant Glide scores may produce significant COVID19 activity for further development, which may prove their therapeutic potential.Copyright © 2020 Bentham Science Publishers.

Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain

The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving transmembrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding;side chain should contain hydrogen donor group;the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids. © 2023 Serbian Chemical Society. All rights reserved.

Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain

The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving trans membrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding;side chain should contain hydrogen donor group;the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids.

IDENTIFICATION OF PROMISING PHYTOCHEMICAL INHIBITORS FOR SARS- CoV-2 FROM ROSA CENTIFOLIA BY INSILICO DOCKING STUDIES

Since November 2019, no cost-effective and potential small drug molecule has been discovered against the SARS-CoV-2 pandemic. The major disadvantage of conventional synthesis is the laborious research time for discovery and development with a huge economy that is not easily met by current pandemic conditions. The main aim of this study is to discover and identify the most effective and promising molecules against the three targets of SARS-CoV-2, such as protease, spike protein and RdRp, via molecular docking screening of various phytochemicals from Rosa Centifolia. The binding affinities were studied using a structure-based drug design of molecular docking. The study results showed that most constituents possess good affinity towards the target than standard drug N3 inhibitor. Among 27 compounds, multiflorin B showed the highest binding energies of -6.975, and -5.471 kcal/mol against protease and RdRp targets, respectively. The compound sabinene showed good interaction with spike protein with a docking score of -4.449 kcal/mol. Molecular ADMET profile estimation showed that the docked phytochemicals are safe. The present study indicates that the various active phytochemical constituents of Rosa Centifolia could inhibit SARS-CoV-2. © 2022 Deuton-X Ltd. All rights reserved.

Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach.

BACKGROUND: In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19, because coronavirus disease 2019 (COVID-19), a life-threatening viral disease, affected first in China and quickly spread throughout the world. In this article, in silico studies have been performed to explore the binding modes of chemical constituents for natural remedies like Curcuma longa (turmeric) and Andrographis paniculata against COVID-19 (PDB ID 5R82) targeting coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by the Glide module, in silico ADMET screening was performed by the QikProp module, and binding energy of ligands was calculated using the Prime MM-GB/SA module. RESULTS: The chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone are significantly binding with the active site of SARS CoV-2 main protease with Glide score more than - 6 when compared to the currently used drugs hydroxychloroquine (- 5.47) and nelfinavir (- 5.93). When compared to remdesivir (- 6.38), cyclocurcumin from turmeric is significantly more active. The docking results of the compounds exhibited similar mode of interactions with SARS CoV-2. Main protease and the residues THR24, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, PHE181, and THR54 play a crucial role in binding with ligands. CONCLUSION: Based on in silico investigations, the chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone, significantly binding with the active site of SARS CoV-2 main protease, may produce significant activity and be useful for further development.

Potential herbs as therapeutic agents for COVID-19: In silico studies

Across 218 countries, since March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a reason for concern. Doctors as well as researchers. stand together to find a treatment for this pandemic. The virus attaches to the host cells via transmembrane spike glycoprotein. The glycoprotein has affinity for human angiotensin-converting enzyme 2 and is dimeric. Thus, the virus attaches to the ACE receptors through the receptor-binding domain (SARS-CoV-2 RBD Spro). Further, the main protease (Mpro), a chymotrypsin-like protease (3CLpro), plays a critical role in post-translational modifications, thereby affecting viral survival. Thus, targeting these viral markers can not only block the fusion with host cells, but also affect replication of the virus. Ancient civilizations have been using plants, herbs as well as spices for their medicinal values as antiviral, antiinflammatory, antipyretic, antimicrobial and many more. The rich array of phytochemicals in these spices endows them with these beneficial properties, and hence they are largely being looked as agents for therapeutic use. However, the journey from laboratory for drug development is a time-consuming process as it starts from trying to identify the major therapeutic component to its pre-clinical studies, clinical and then its marketing as a drug. In the current pandemic where loss of human life has been in millions, a faster and more efficient modality like in silico studies can help escalate this search for a therapy thereby saving mankind. This study is a comprehensive review on results of in silico approaches conducted in near future in an attempt to evolve an ideal therapeutic candidate for ending the pandemic. Results of research conducted on phytochemicals from medicinal and aromatic plants as potential therapeutic candidates using tools of bioinformatics and computational modelling are hereby discussed.

In Silico Study and Excito-Repellent Activity of Vitex negundo L. Essential Oil against Anopheles gambiae

(1) Background: Essential oil from Vitex negundo is known to have repellent and insecticidal properties toward the Anopheles gambiae and this is linked to its monoterpene and sesquiterpene content. In this work, an effort is made to delineate the constitution of V. negundo essential oil (VNEO) and their interaction with odorant-binding proteins (OBPs) of A. gambiae and hence access its repellent efficiency as cost-effective and safer malaria vector control alternatives. (2) Methods: Anopheles species authentication was performed by genomic DNA analysis and was subjected to behavioral analysis. GC-MS profiling was used to identify individual components of VNEO. Anopheles OBPs were obtained from the RCSB protein data bank and used for docking studies. Determination of ligand efficiency metrics and QSAR studies were performed using Hyper Chem Professional 8.0.3, and molecular dynamics simulations were performed using the Desmond module. (3) Results: GC-MS analysis of VNEO showed 28 compounds (monoterpenes, 80.16%;sesquiterpenes, 7.63%;and unknown constituents, 10.88%). The ligand efficiency metrics of all four ligands against the OBP 7 were within acceptable ranges. β-selinene (−12.2 kcal/mol), β-caryophellene (−9.5 kcal/mol), sulcatone (−10.9 kcal/mol), and α-ylangene (−9.3 kcal/mol) showed the strongest binding affinities for the target proteins. The most stable hydrophobic interactions were observed between β-selinene (Phe111 and Phe120), Sulcatone (Phe54 and Phe120), and α-ylangene (Phe111), while only sulcatone (Tyr49) presented H-bond interactions in the simulated environment. (4) Conclusions: Sulcatone and β-caryophyllene presented the best log p values, 6.45 and 5.20, respectively. These lead phytocompounds can be used in their purest as repellent supplement or as a natural anti-mosquito agent in product formulations.

Repurposing Thalidomide, Its Analogue And Apremilast For Possible Antiviral In Situation Of Severe Covid Cytokine Syndrome.

BACKGROUND: COVID-19, caused by SARS-corona virus-2, is a global wide expanded public health risk at a bizarre level. In this current situation, COVID-19 became a serious emerging pandemic. Choosing drug reusing is a crucial step in identifying the new uses of old established drugs. To achieve a significant and healthy way of treatment in COVID patients within a short duration, drug repurposing is a novel method. OBJECTIVE: The present study concentrated on the molecular docking of thalidomide and its analogues and Apremilast against Coronavirus infectious symptoms, evaluated on virus proteins (Spike Protein, 3cl Protease, Nucleocapsids). METHODS: The present study explores the possibility of repurposing thalidomide for the treatment of SARS-COV-2 infection by assessing and confirming with docking affinity scores of thalidomide & its analogues and Apremilast, with spike protein, 3cl protease, and nucleocapsids. RESULTS: From the study results, thalidomide, pomalidomide, lenalidomide, and Apremilast exhibited better binding affinity to N Protein (4KXJ), Protease (4WY3) and Spike Protein (5WRG). In comparison of targets, N Protein - 4KXJ is the best for the four ligands. It is finalized that all four ligands (Thalidomide - -8.6, Pomalidomide - -8.8, Lenalidomide,and - -8.2,and Apremilast - -8.1) have good docking scores with the target N Protein. CONCLUSION: The present study shows confirmation that thalidomide and its analogues and apremilast as a better fit for treating high risk patients of COVID -19 viral infection which are supposed to promote beneficial effects for both respiratory illnesses like COVID-19 symptoms as well as improve the pathological state of condition.

SYNTHESIS AND MOLECULAR DOCKING STUDIES ON DIFFERENT THIOZOLIDINONE DERIVATIVES OF BENZILIC ACID

Viral diseases continue to cause serious morbidity and mortality worldwide. For several virus infections, no antiviral medications are presently available especially for Covid-19. There is a clear need for new antiviral agents with new mechanisms of action or broad-spectrum activity, to face the issues of drug-resistant mutant viruses or emerging and neglected viruses. The benzilic acid thiazolidinone derivatives were prepared by reaction of alkyl/arylthiosemicarbazides with 2-bromopropionate in the presence of anhydrous sodium acetate in absolute ethanol from benzilic acid hydrazide. Compounds, which consist of (–C=N–N–) – the two interlinked nitrogen atoms, have been found to possess many biological activities. Viral diseases continue to cause serious morbidity and mortality worldwide. For several virus infections, no antiviral medications are presently available especially for Covid-19. There is a clear need for new antiviral agents with new mechanisms of action or broad-spectrum activity, to face the issues of drug-resistant mutant viruses or emerging and neglected viruses. The present work is an extension of our ongoing efforts toward developing promising biologically active agents using a hybrid pharmacophore approach. © 2022, Scibulcom Ltd.. All rights reserved.

Exploring the Binding Interaction of Active Compound of Pineapple against Foodborne Bacteria and Novel Coronavirus (SARS-CoV-2) Based on Molecular Docking and Simulation Studies.

Natural resources, particularly plants and microbes, are an excellent source of bioactive molecules. Bromelain, a complex enzyme mixture found in pineapples, has numerous pharmacological applications. In a search for therapeutic molecules, we conducted an in silico study on natural phyto-constituent bromelain, targeting pathogenic bacteria and viral proteases. Docking studies revealed that bromelain strongly bound to food-borne bacterial pathogens and SARS-CoV-2 virus targets, with a high binding energy of -9.37 kcal/mol. The binding interaction was mediated by the involvement of hydrogen bonds, and some hydrophobic interactions stabilized the complex and molecular dynamics. Simulation studies also indicated the stable binding between bromelain and SARS-CoV-2 protease as well as with bacterial targets which are essential for DNA and protein synthesis and are required to maintain the integrity of membranous proteins. From this in silico study, it is also concluded that bromelain could be an effective molecule to control foodborne pathogen toxicity and COVID-19. So, eating pineapple during an infection could help to interfere with the pathogen attaching and help prevent the virus from getting into the host cell. Further, research on the bromelain molecule could be helpful for the management of COVID-19 disease as well as other bacterial-mediated diseases. Thus, the antibacterial and anti-SARS-CoV-2 virus inhibitory potentials of bromelain could be helpful in the management of viral infections and subsequent bacterial infections in COVID-19 patients.

Synthesis, spectroscopic characterization of novel phthalimides derivatives bearing a 1,2,3-triazole unit and examination as potential SARS-CoV-2 inhibitors via in silico studies.

In the present study, novel phthalimide derivatives 8(a-f) and 9(a-f) bearing a 1,2,3-triazole subunit were synthesized via CuAAC reactions and characterized by 1H, 13C NMR, HR-MS, and FT-IR analyses. To support the fight against SARS-CoV-2, in silico molecular docking studies were carried out to examine their interactions with the proteins of SARS-CoV-2 (Mpro and PLpro) and the protein-protein interactions (PPI) between the ACE2-spike (S1) in comparison with various inhibitors reported to be active by in vitro experiments. The ligand-protein stabilities of compounds 8a-Mpro, 8b-PLpro, and 9a-'ACE2-S1' showing the best binding energy and predicted inhibition constant values (Ki) were examined by molecular dynamics simulation studies. Finally, in silico ADMET properties of the target compounds were investigated using the Swiss ADME and ProTox-II web tools. According to in silico results, all phthalimide analogs may block the PPI between S1 and ACE2. The compounds may also inhibit the progression of the Mpro, and PLpro proteins of SARS-CoV-2. Additionally, it has been estimated that the compounds are suitable for oral administration and exhibit low levels of toxicity.

Synthesis, Characterization, Biological Activity and Molecular Docking Studies of Novel Organotin(IV) Carboxylates.

Four new carboxylates complexes with general formula R2SnL2 and R3SnL, where R = n-butyl (1, 3), methyl (2, 4) and L = 4-Chlorophenoxyacetate, were synthesized in significant yields. FT-IR analysis revealed a chelating (1 and 2) and a bridging bidentate (3 and 4) coordination modes for the carboxylate ligand in solid state which was further confirmed by the single crystal X-ray analysis of complex 4. The NMR data (1H, 13C and 119Sn) revealed a higher coordination number around the tin center in R2SnL2 (1 and 2) compared to R3SnL (3 and 4). A close matching was observed between the experimental and calculated structures (obtained at B3LYP/6-31G* + LANL2DZ basis set). Quantum chemical analysis indicates that the carboxylate moiety has the major contribution in the formation of filled and unfilled orbitals as well as in ligand to ligand intramolecular charge transfer during the electronic transitions. The cytotoxicity data of the screened compounds evaluated against lung cancer cell line (A549) and normal lung fibroblast cell line (MRC-5) revealed that 1, 3 and 4 have shown dose dependent cytotoxic effects while HL and 2 have shown steady and low cytotoxic activities. The antibacterial activity of complexes 1-4 is higher than that of HL. Molecular docking study showed an intercalation binding mode for complex 3 with DNA (docking score = -3.6005) involving four polar interactions. Complex 3 docking with tubulin (PDB ID 1SA0) with colchicine as a target protein resulted in three polar interactions (docking score -5.2957). Further, the docking analysis of the HL and 1-4 has shown an adequate interactions with the coronavirus SARS-CoV-2 spike protein, nucleocapsid protein and human angiotensin converting enzyme (ACE2).

Synthesis, Cytotoxicity, Molecular Docking, Molecular Simulation and ADME Properties of Cinnamoylated Chloroquine Hybrid Analogues as Corona Virus Protease Inhibitors

In an attempt to challenge COVID-19, molecular docking of cinnamoylated chloroquine compounds 1-15 against main protease (Mpro) enzyme of SARS-CoV-2 was undertaken. To study the stability of the complex formed between the drug and the receptor, suitable docking possesses were selected and put into molecular dynamics studies. Further ADME properties were determined using SWISS ADME software. In the docking studies compounds 5, 9, 14 and 15 exhibited encouragable binding with the Mpro crystal structure with docking scores of -8.1, -7.9, -7.8 and -7.9 Kcal/mole respectively. It was observed that CYS145 and GLU166 played a significant role during the interaction of molecules with the active site of COVID-19Mpro. Among compounds 5, 9, 14 and 15, compound 5 had stable interactions with the protein, which might be the reason for the optimum RMSD, RMSF, radius of gyration and protein-ligand contacts (hydrogen bonding) values. The compound 5 was synthesised and tested for its cytotoxic activity against fibroblast L929 cell line. The above study indicated that the compound 5 as a promising agent, and during the drug discovery process it could be taken as a starting point for lead optimization.

Activity of Isoxazole substituted 9-aminoacridines against SARS CoV-2 main protease for COVID19: A computational approach

Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease affected first in china and quickly spread throughout the world in early 2020. So many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19.In the present article, in-silico studies have been performed to explore the binding modes of Isoxazole substituted 9-aminoacridines(1a-x) against SARS CoV-2 main protease (PDB id-5R82) targeting corona virus using Schrodinger suit 2019-4. The docking studies are performed by Glide module, in-silico ADMET screening was performed by qik prop module and the binding energy of ligands was calculated using PRIME MM-GB/SA module. From the results, Isoxazole substituted 9-aminoacridines like 1n,f,c,k,h,a,e,g,b,d are significantly active against SARS CoV-2 main protease with Glide score more than-5.5 when compared with currently recommended drug for COVID19 Hydroxy chloroquine (G score-5.47) and Co crystallized ligand CID_24701445 (G score-4.4). The docking results of the compounds exhibited similar mode of interactions with COVID19 and the residues THR24, THR25, THR26, SER46, MET49, HIE41, GLN189, ARG189, ASP187, MET168, HIE164, ASN142 and GLY143 play a crucial role in binding with ligands. © 2021 DSR Publishers/The University of Jordan. All Rights Reserved.

Ginger from Farmyard to Town: Nutritional and Pharmacological Applications.

Ginger (Zingiber officinale) is one of the most widely used natural products consumed as a spice and medicine for treating diabetes, flatulent intestinal colic, indigestion, infertility, inflammation, insomnia, a memory booster, nausea, rheumatism, stomach ache, and urinary tract infections. To date, over 400 bioactive components, such as diarylheptanoids, gingerol analogues, phenylalkanoids, sulfonates, monoterpenoid glycosides, steroids, and terpene compounds have been derived from ginger. Increasing evidence has revealed that ginger possesses a broad range of biological activities, especially protective effects against male infertility, nausea and vomiting, analgesic, anti-diabetic, anti-inflammatory, anti-obesity, and other effects. The pharmacological activities of ginger were mainly attributed to its active phytoconstituents such as 6-gingerol, gingerdiol, gingerol, gingerdione, paradols, shogaols, sesquiterpenes, zingerone, besides other phenolics and flavonoids. In recent years, in silico molecular docking studies revealed that gingerol (6-gingerol, 8-gingerol, and 10-gingerol) and Shogaol (6-shogaol, 8-shogaol, 10-shogaol) had the best binding affinities to the receptor protein in disease conditions such as diabetes, inflammation, obesity, and SARS-CoV-2. Furthermore, some clinical trials have indicated that ginger can be consumed for alleviation of nausea and vomiting induced by surgery, pain, diabetes, obesity, inflammation, male infertility. This review provides an updated understanding of the scientific evidence on the development of ginger and its active compounds as health beneficial agents in future clinical trials.