Synthesis,Characterization, Antimicrobial Activity,and Docking Studies of New Triazolic Tripodal Ligands

The synthesis and characterization of new N‐donor bitriazolic tripods were reported. The in vitro antibacterial and antifungal activities of these products were screened against fungal strain (Candida pelliculosa) and against four bacterial strains (Micrococcus luteus, Bacillus subtilis, Listeria innocua, and Escherichia coli). Biological data revealed the effect of the chemical structure on antimicrobial activity. Molecular docking studies of some compounds showed that they could act as inhibitors for the biotin carboxylase enzyme.     

Synthesis,Antimicrobial Activities,and Molecular Docking Studies of Dihydrotriazine Derivatives Bearing a Quinoline Moiety

In this article, three series of dihydrotriazine derivatives bearing a quinoline moiety ( 5a , 5b , 8a – 8c , and 9a – 9m ) have been designed, synthesized, and evaluated as antibacterial agents. Compounds 8a – 8c were found to be the most potent of all of the compounds tested with an MIC value of 1 μg/mL against several Gram‐positive (S. aureus 4220 and MRSA CCARM 3506) and Gram‐negative (E. coli 1924) strains of bacteria. In addition, 3‐[4‐amino‐6‐(phenethylamino)‐2,5‐dihydro‐1,3,5‐triazin‐2‐yl)‐6‐[(3‐chlorobenzyl)oxy]quinolin‐2‐ol ( 8a ) showed potent inhibitory activity (MIC=2 μg/mL) against Pseudomonas aeruginosa 2742, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. Structure‐activity relationships (SAR) analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency of the quinoline compounds. In vitro enzyme study implied that compound 8a also displayed DHFR inhibition.     

Antimicrobial Pyridazines: Synthesis,Characterization, Cytotoxicity,Substrate Promiscuity,and Molecular Docking

A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, ¹H‐ and ¹³C‐NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram‐negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892–3.744 μg/mL) lower than that of chloramphenicol (2.019–8.078 μg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC₅₀>64 μg/mL). MOE docking studies showed a good overlay of these new pyridazines with co‐crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).     

Design,Synthesis, Molecular Docking,and Molecular Dynamics Simulation Studies of Novel 3-Hydroxypyridine-4-one Derivatives as Potential Acetylcholinesterase Inhibitors

Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin-4-one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1-(4-methoxyphenethyl)piperidin-4-yl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one (VII_d) showed weaker but promising AChE inhibition compared to donepezil (IC₅₀=143.090 nM). The average RMSD values of VII_d was found to be 2.25 indicated less structural changes in the active site residues. The phenyl group of the phenyl-ethyl-N-piperidine moiety of VII_d formed hydrophobic interactions with Trp285 and Tyr340. There was a π-cation interaction between nitrogen atom of piperidine ring and Phe294. Another π-cation interaction was found between type 2 amine of linker and Trp85. Piperidine ring interacted with Tyr336, Tyr123, and Phe337 through hydrophobic interactions. Indeed, the VII_d was predicted to be absorbed across the gastrointestinal tract, though it may be pumped out by P-gp. Indeed, VIId can permeate through the blood brain barrier. MD simulation studies revealed that benzyloxy moiety plays a role similar to benzylpiperidine moiety of donepezil in binding to the active site residues. Also, carbonyl group functioned similar to indanone ketone group. Overall; further research on VII_d may lead to introduction of a novel class of AChE inhibitors.     

Synthesis and Evaluation of Antimicrobial Activity of Some Pyrimidine Glycosides

Reaction of ethyl 4-thioxo-3,4-dihydropyrimidine-5-carboxylate derivatives 1a,b and ethyl 4-oxo-3,4-dihydropyrimidine-5-carboxylate 1c with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in KOH or TEA afforded ethyl 2-aryl-4-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosylthio or/ oxy)-6-methylpyrimidine-5-carboxylate 6a-c. The glucosides 6a and 6b were obtained by the reaction of 1a and 1b with peracetylated glucose3 under MW irradiation. Mercuration of 1a followed by reaction with acetobromoglucose gave the same product 6a. The reaction of 1a-c with peracetylated ribose 4 under MW irradiation gave ethyl 2-aryl-4-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosylthio)-6-methylpyrimidine-5-carboxylate 8a–c. The deprotection of 6a–c and 8a–c in the presence of methanol and TEA/H₂O afforded the deprotected products 7a–c and 9a–c. The structure were confirmed by using ¹H and ¹³CNMR spectra. Selected members of these compounds were screened for antimicrobial activity.     

Synthesis,Molecular Docking and Preliminary Antileukemic Activity of 4-Methoxybenzyl Derivatives Bearing Imidazo[2,1-b][1,3,4]thiadiazole

In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1-b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate and 6-(4-chlorophenyl)-2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC₅₀ values ranging between 0.79 and 1.6 μM. The results indicate that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate is inducing phosphatidylserine externalization and caspase-3 activation which are both a hallmark of apoptosis. Docking studies showed that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate binds within the active sites of transforming growth factor beta (TGF-β) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions.     

Design,Synthesis, Docking Study of Pyrazolohydrazinopyrimidin-4-one Derivatives and Their Application as Antimicrobials

New series of pyrazoles 4a – c and pyrazolopyrimidines 5a – f had been constructed. The newly synthesized compounds were assessed for their antimicrobial activity towards E. coli and P. aeruginosa (gram –ve bacteria), B. subtilis and S. aureus (gram +ve bacteria) and A. flavus and C. albicans (representative of fungi). The pyrazolylpyrimidine-2,4-dione derivative 5b is the most active candidate against B. subtilis (MIC=60 μg/mL) and P. aeruginosa (MIC=45 μg/mL). Regarding antifungal potential, compound 5f was the most effective against A. flavus (MIC=33 μg/mL). Similarly, compound 5c displayed strong antifungal activity towards C. Albicans (MIC=36 μg/mL) in reference to amphotericin B (MIC=60 μg/mL). Finally, the novel compounds had been docked inside dihydropteroate synthase (DHPS) to suggest the binding mode of these compounds.     

Antiproliferative Noscapinoids Bearing an Amidothiadiazole Scaffold as Apoptosis Inducers: Design,Synthesis and Molecular Docking

Noscapine an FDA-approved antitussive agent. With low cytotoxicity with higher concentrations, noscapine and its derivatives have been shown to have exceptional anticancer properties against a variety of cancer cell lines. In order to increase its potency, in this study, we synthesized a series of new amido-thiadiazol coupled noscapinoids and tested their cytotoxicity in vitro. All of the newly synthesised compounds demonstrated potent cytotoxic potential, with IC₅₀ values ranging from 2.1 to 61.2 μM than the lead molecule, noscapine (IC₅₀ value ranges from 31 to 65.5 μM) across all cell lines, without affecting normal cells (IC₅₀ value is>300 μM). Molecular docking of all these molecules with tubulin (PDB ID: 6Y6D, resolution 2.20 Å) also revealed better binding affinity (docking score range from −5.418 to −9.679 kcal/mol) compared to noscapine (docking score is −5.304 kcal/mol). One of the most promising synthetic derivatives 6aa (IC₅₀ value ranges from 2.5 to 7.3 μM) was found to bind tubulin with the highest binding affinity (ΔG_binding is −28.97 kcal/mol) and induced apoptosis in cancer cells more effectively.     

Matrix-Metalloproteinase Inhibitory Study of Novel Tetrahydroisoquinoline-4-carboxylates: Design,Synthesis, and Molecular Docking Studies

The design, molecular docking, synthesis and structure-activity relationship (SAR) of a series of novel methyl 1-oxo-2-(propan-2-yl)-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylates, were investigated for antiproliferative and cytotoxic studies by screening against cancer cell lines of different origin by MTT, LDH and Trypan Blue Assay. Irrespective of cell lines, among the synthesized nonpeptido-mimetic analogs 5a – e , 5c has executed potent bio-potency with IC₅₀ value of 7.00 to 7.21 μM, which further expressed in-vivo anti-tumor activity against murine T-cell lymphoma cell lines (Daltons Lymphoma-DLA) by regressing tumor growth. The formation of neovessels from the vasculogenesis was diminished reflecting the antitumor activity. The neovessel formation is directly relied on expression of matrix meteloproteases (MMP's) level which was drastically reduced by 5c treatment as evaluated by immonoblot assays. This is further supported by in-silico ADMET studies performed by ACD I-Lab 2.0 were in agreement with Lipinski rule of five. Reporting results were assessed as a positive parameter for further validation of the compound for therapeutic potential of cancer by 5c for preclinical studies in near future.     

Norfloxacin Analogues: Drug Likeness,Synthesis, Biological,and Molecular Docking Assessment

Russian Journal of Bioorganic Chemistry - Norfloxacin (I) and its 1,3,4-oxadiazole, thiazolidin-4-one, 1,3,4-oxadiazoline, 1,2,4-triazole, Schiff’s base, hydrazide and 1,3,4-thiadiazole...     

Synthesis,Biological Activity Evaluation and Molecular Docking of Imidazole Derivatives Possessing Hydrazone Moiety

In an attempt to identify potential active anticancer agents with low cytotoxic properties and CA inhibitors, a new series of hybrid compounds incorporating imidazole ring and hydrazone moiety as part of their structure were synthesized by aza-Michael addition reaction followed by intramolecular cyclization. The structure of synthesized compounds was elucidated using various spectral techniques. Synthesized compounds were evaluated for their in vitro anticancer (prostate cell lines; PC3) and CA inhibitory (hCA I and hCA II) activity. Among them, some compound displayed remarkable anticancer activity and CA inhibitory activity with K_i values in range of 17.53±7.19–150.50±68.87 nM against cytosolic hCA I isoform associated with epilepsy, and 28.82±14.26–153.27±55.80 nM against dominant cytosolic hCA II isoforms associated with glaucoma. Furthermore, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness qualities. The proteins used for the calculations are prostate cancer protein (PDB ID: 3RUK and 6XXP). ADME/T analysis was carried out to examine the drug properties of the studied molecules.     

Design,Synthesis, In Silico Docking Studies,and Antibacterial Activity of Some Thiadiazines and 1,2,4-Triazole-3-Thiones Bearing Pyrazole Moiety

Russian Journal of Bioorganic Chemistry - In view of developing new bioactive compounds, a series of...     

Novel Penicillin Analogues as Potential Antimicrobial Agents; Design,Synthesis and Docking Studies

A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC₅₀ value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.     

Design,Synthesis, and Antitumor Activity Evaluation of Trifluoromethyl-Substituted Pyrimidine Derivatives Containing Urea Moiety

Russian Journal of Bioorganic Chemistry - In order to find efficient new antitumor drugs, a series of novel pyrimidine derivatives containing urea moiety were designed and synthesized, and the...     

Design,Synthesis and Cytotoxicity of New Coumarin-1,2,3-triazole Derivatives: Evaluation of Anticancer Activity and Molecular Docking Studies

A library of new coumarin-1,2,3-triazole hybrids 7a – l were synthesized from 4-(diethylamino)-2-hydroxybenzaldehyde precursor through a series of reactions including Vilsmeier-Haack reaction and condensation reaction to achieve key intermediate oxime and further performed click reaction by using different aromatic azides. We screened all molecules in silico against crystal structure of Serine/threonine-protein kinase 24 (MST3), based on these results all molecules were screened for their cytotoxicity against human breast cancer MCF-7 and lung cancer A-549 cell lines. Compound 7 b (p-bromo) showed best activity against both cell lines MCF-7 and A-549 with IC₅₀ value of 29.32 and 21.03 μM, respectively, in comparison to Doxorubicin corresponding IC₅₀ value of 28.76 and 20.82 μM. Another compound 7 f (o-methoxy) also indicated good activity against both cell lines with IC₅₀ value of 29.26 and 22.41 μM. The toxicity of all compounds tested against normal HEK-293 cell lines have not shown any adverse effects.     

Microwave-Assisted Synthesis and Molecular Docking Studies of Fluorinated 1,3,4-Oxadiazole Derivatives as Antimicrobial Agent

Russian Journal of Bioorganic Chemistry - A series of phenyl-5-(2,3,5,6-tetrafluoro-phenyl)-[1,3,4]-oxadiazole were prepared from 2,3,5,6-tetrafluoro-benzoic acid hydrazide by treatment with...     

Synthesis,Characterization, Molecular Docking,and Biological Activities of Some Natural and Synthetic Urolithin Analogs

Urolithins (that is, hydroxy substituted benzo[c]chromen‐6‐one derivatives) are formed within the gastrointestinal tract following to the exposure to various ellagitannin rich diet, particularly involving pomegranate, nuts, and berries. Regarding the bioavailability deficiency of ellagitannins, the biological activities obtained through the extracts of these dietaries are attributed to the urolithin compounds, since they are bioavailable. Particularly, there are studies indicating the importance of ellagitannin‐rich food for protective and alternative treatment of Alzheimer's Disease (AD). From this perspective, within this study, the major urolithins (that is, urolithins A and B), their methyl ether metabolites, as well as some synthetic urolithin analogs have been synthesized and screened for their biological activities in various enzyme inhibition (acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, cyclooxygenase 1, and cyclooxygenase 2) and antioxidant (DPPH radical scavenging) assay systems. The results pointed out the potential of urolithins to act as inhibitors on these receptors. Docking studies were also performed to investigate the possible interactions.     

Design,Synthesis, Molecular Docking Studies,and Biological Evaluation of Pyrazoline Incorporated Isoxazole Derivatives

Russian Journal of Bioorganic Chemistry - A novel series of pyrazoline incorporated isoxazole derivatives were designed and synthesized. The synthesized compounds were characterized by 1H NMR, IR...     

Synthesis,Molecular Properties Prediction and Antimicrobial Activity of Imidazolyl Schiff Bases,Triazoles and Azetidinones

Benzylidenehydrazinyl imidazoles ( 3 ) are prepared from 2‐hydrazinyl imidazoles ( 2 ) on treatment with hydrazine. The imine functionality in 3 is utilized to develop 5′‐aryl‐N‐(4‐aryl‐1H‐imidazol‐2‐yl)‐1H‐1,2,3‐triazol‐1‐amines ( 5 ) by 1,3‐dipolar cycloaddition of diazomethane followed by aromatization with I₂ in DMSO. Compounds 3 are also explored to prepare 4′‐aryl‐1‐(4‐aryl‐1H‐imidazol‐2‐ylamino)‐3‐chloroazetidin‐2‐ones ( 6 ) on treatment with chloroacetyl chloride. The Molinspiration calculations predicted that 3 , 5 and 6 have molecular hydrophobicity, conformational flexibility, good intestinal absorption and bioactivity scores. The chloro, bromo and nitro substituted imidazolyl azetidinones ( 6c , 6d , 6f ) and nitro substituted imidazolyl triazole ( 5f ) exhibited excellent antibacterial activity on B. subtilis, whereas chloro and nitro substituted imidazolyl triazoles ( 5c , 5f ) showed prominent antifungal activity on A. niger.