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.

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.

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.

Theoretical, in Vitro Antiproliferative, and in Silico Molecular Docking and Pharmacokinetics Studies of Heteroleptic Nickel(II) and Copper(II) Complexes of Thiosemicarbazone-Based Ligands and Pefloxacin.

Twelve new heteroleptic nickel(II) and copper(II) complexes of the type [M(L1-6 )(Pfx)2 ] (1-12), where L1-6 =2-benzylidenehydrazinecarbothioamide (L1 ), 2-benzylidene-N-methylhydrazinecarbothioamide (L2 ), 2-benzylidene-N-phenylhydrazinecarbothioamide (L3 ), 2-(4-methylbenzylidene)hydrazinecarbothioamide (L4 ), 2-(4-methylbenzylidene)-N-methylhydrazinecarbothioamide (L5 ) and 2-(4-methylbenzylidene)-N-phenylhydrazinecarbothioamide (L6 ), Pfx=pefloxacin and M=Ni(II) or Cu(II) have been synthesised, and their structures were confirmed by different spectral techniques. The spectral data and density functional theory (DFT) calculations supported the bonding of pefloxacin drug molecule via one of the carboxylate oxygen atoms and the pyridone oxygen atom, and the thiosemicarbazone ligand via the imine nitrogen and the thione sulfur atoms with the metal(II) ion, forming distorted octahedral geometry. In vitro antiproliferative activity of the synthesized complexes was evaluated against three human breast cancer (T47D, estrogen negative (MDA-MB-231) and estrogen positive (MCF-7)) as well as non-tumorigenic human breast epithelial (MCF-10a) cell lines, which showed the higher activity for the copper(II) complexes. The interaction of the synthesized complexes with an oncogenic protein H-ras (121 p) was explored by in silico molecular docking studies. Further, in silico pharmacokinetics and ADMET parameters were also analysed to predict the drug-likeness as well as non-toxic and non-carcinogenic behavior, and safe oral administration of the complexes.

In vitro anti-proliferative, and in silico ribonucleotide reductase and pharmacokinetics studies of heteroleptic silver(I), nickel(II) and copper(II) complexes of 4-methyl-3-thiosemicarbazones and ibuprofen.

OBJECTIVES: The present research focuses on the in vitro anti-proliferative, and in silico ribonucleotide reductase and pharmacokinetics studies of twelve heteroleptic metal complexes of the general formulae [Ag(L1-4)(ibu)] (1-4) and [M(L1-4)(ibu)2] (5-12), where L1-4 = 2-(1-(4-substitutedphenyl)ethylidene)-N-methylhydrazinecarbothioamide, ibu = non-steroidal anti-inflammatory drug (ibuprofen), and M = Cu(II) and Ni(II). METHODS: Various spectroscopic techniques were used to authenticate the structure of the synthesized complexes. UV-Vis and cyclic voltammetry techniques were used to analyse the stability and the reducing ability of the complexes. In vitro anti-proliferative studies by MTT assay, apoptotic behaviour and cellular uptake studies were investigated followed by the in silico interaction with ribonucleotide reductase (RNR) enzyme. RESULTS: The spectral studies predicted distorted tetrahedral geometry around silver(I) ion and distorted octahedral geometry around nickel(II) and copper(II) ions. The reducing ability of the copper(II) complexes was analysed using ascorbic acid by UV-Vis and cyclic voltammetry techniques, which authenticate the reducing ability of the complexes and the possible interactions within the cells. The in vitro anti-proliferative activity of the synthesized complexes against three cancerous (estrogen positive (MCF-7), estrogen negative (MDA-MB-231) and pancreatic (PANC-1)) and one normal (MCF-10a) cell lines by MTT assay showed enhanced activity for copper(II) complexes 11 and 12 containing the hydrophobic substituents. The apoptotic and cellular uptake studies showed that the complex 12 is readily taken up by PANC-1 cell lines and induces ROS-mediated mitochondrial and caspase-dependent apoptosis. The in silico studies indicated hydrogen bonding, hydrophobic and π-pair (π-π, π-σ and π-cation) interactions between the complexes and the ribonucleotide reductase (RNR) enzyme. The in silico pharmacokinetics studies of the complexes predicted the drug-likeness characteristics of the complexes. CONCLUSION: The synthesized complexes are found to be less toxic to normal cells and inhibit the growth of cancerous cells by inducing mitochondrial-mediated and caspase dependent apoptotic pathway in PANC-1 cells.

Multi-target activity of copper complexes: Antibacterial, DNA binding, and molecular docking with SARS-CoV-2 receptor.

A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL1-3(diimine)] (1-6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H2L1), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H2L2) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H2L3) with diimine = 2,2'-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the presence of copper(II) chloride and analyzed using various spectroscopic methods. All the spectroscopic results support that the complexes adopt a pentagonal-bipyramidal shape around the copper ion. Gram-positive and Gram-negative bacteria were used to test all the complexes for antibacterial activity and all the complexes had greater potency against gram-negative pathogens. DNA-binding experiments of complexes with calf thymus DNA revealed a major-groove binding pattern, further supported by molecular docking studies. Complexes have significantly interacted with SARS-CoV-2 receptor via π-π, π-σ, π-alkyl, π-anion, π-cation, alkyl, hydrogen bond, van der Waals, and electrostatic interactions. The estimated binding energy and inhibition constant of these complexes are higher than standard drugs, chloroquine, and molnupiravir.

Silver(I) metallodrugs of thiosemicarbazones and naproxen: biocompatibility, in vitro anti-proliferative activity and in silico interaction studies with EGFR, VEGFR2 and LOX receptors.

Four new heteroleptic silver(I) complexes with the general formula [Ag(L1-4)(nap)] (1-4), where L1-4 =  2-(1-(4-substitutedphenyl)ethylidene)hydrazinecarbothioamide and nap = naproxen, have been synthesized and characterized. The geometric parameters determined from density functional theory and UV-Vis studies indicate distorted tetrahedral geometry around silver(I) ion. Fourier transform infrared (FT IR) spectra evidenced asymmetric bidentate coordination mode of carboxyl oxygen atoms of naproxen with silver(I) ion. The complexes are stable for 72 h and biocompatibility was analysed towards normal human dermal fibroblast cells, which showed non-toxic nature up to 100 ng/ml. In vitro anti-proliferative activity of the complexes by MTT assay was tested against three human cancerous cell lines and one non-tumorigenic human breast epithelial cell line (MCF-10a) in which the complex 4 exhibited enhanced activity. The morphological changes observed by acridine orange/ethidium bromide and Hoechst 33258 staining method reveal apoptosis-inducing ability of the complexes. The molecular docking studies suggest hydrogen bonding, hydrophobic and π-pair interactions with the active site of epidermal growth factor receptor, vascular endothelial growth factor receptor 2 and lipoxygenase receptors.

Biocompatibility, in Vitro Antiproliferative, and in Silico EGFR/VEGFR2 Studies of Heteroleptic Metal(II) Complexes of Thiosemicarbazones and Naproxen.

Eight heteroleptic nickel(II) and copper(II) complexes of the type [M(L1-4)(nap)2] (1-8), where L1-4 = 2-(1-(4-substitutedphenyl)ethylidene)hydrazinecarbothioamide, nap = naproxen, and M = Ni(II) or Cu(II), have been synthesized and characterized. UV-vis and EPR spectral studies showed distorted octahedral geometry around metal(II) ions. The cyclic voltammogram of complexes 1-8 displayed an irreversible one-electron transfer process in the cathodic region (Epc = -0.66 to -1.43 V), and nickel(II) complexes 1-4 displayed an irreversible one-electron oxidation process in the anodic region (Epa = 0.75 to 1.10 V). The obtained magnetic moment values (1.82-1.93 µB) for copper(II) complexes 5-8 indicate distortion from octahedral geometry, which is further supported by EPR studies. The geometry of the complexes is retained in both solid and solution phases as evidenced from UV-vis and EPR studies. All the complexes showed stability for almost 72 h in biologically relevant solutions. The reducing ability of the copper(II) complexes in the presence of ascorbic acid was analyzed by UV-vis and cyclic voltammetry techniques, which indicates the reduction of the copper(II) to a copper(I) center, and possible interaction within the cells. An in vitro antiproliferative study revealed the nontoxic nature of complexes to normal human dermal fibroblast (NHDF) up to a concentration of 100 ng/mL. The antiproliferative activity of the complexes was tested against three cancerous (human breast adenocarcinoma (MCF-7), hepatoma (HepG2), and lung (A549)) cell lines using MTT reduction assay, which showed enhanced activity for complexes 4 and 8 containing the hydrophobic substituent. Apoptotic and cellular uptake studies showed that complex 8 is readily taken up by HepG2 cell lines and induces ROS-mediated mitochondrial and caspase-dependent apoptosis. In silico studies indicated hydrogen bonding, hydrophobic, and π-pair (π-π, π-σ, and π-cation) interactions between the complexes and EGFR/VEGFR2 kinase receptors.

DNA profiling and in vitro cytotoxicity studies of tetrazolo[1,5-a]pyrimidine-based copper(II) complexes.

A series of N-benzoylated mononuclear copper(II) complexes of the type [Cu(L1-6)Cl2] (1-6), where L1= ethyl 4-benzoyl-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L2= ethyl 4-(4-nitrobenzoyl)-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L3 = ethyl 4-benzoyl-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L4 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L5 = ethyl 4-benzoyl-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate and L6 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate have been synthesized and characterized by spectral methods. Electron paramagnetic resonance spectra of complexes show four lines, characteristic of square planar geometry. The binding studies of the complexes with calf thymus DNA (CT-DNA) revealed groove mode of binding, which were further supported by molecular docking studies. Gel electrophoresis experiments demonstrated the ability of the complexes to cleave plasmid DNA in the absence of activators. Further, the cytotoxicity activity of the complexes were examined on three cancerous cell lines (lung (A549), cervical (HeLa) and colon (HCT-15)), and on two normal cells (human embryonic kidney (HEK) and peripheral blood mononuclear cells (PBMC)) by MTT assay.

Copper complexes as prospective anticancer agents: in vitro and in vivo evaluation, selective targeting of cancer cells by DNA damage and S phase arrest.

A series of six new bis(thiosemicarbazone)copper(i) complexes of the type [Cu(L1-6)2Cl] (1-6) have been synthesized and characterized. The molecular structure of the ligand L4 was determined by the single crystal XRD method. All the complexes adopted trigonal planar (Y-shaped) geometry. All the complexes strongly bind with CT-DNA via intercalative mode, which was further supported by molecular docking studies. Further, the complexes were effectively bind with BSA as observed by UV-Vis and fluorescence spectra. All the complexes effectively cleave pBR322 DNA through hydrolytic pathway as evidenced from T4 ligase experiments. All the complexes interact with the anticancer receptor focal adhesion kinase (FAK) via electrostatic, van der Waals, hydrogen bonding, σ-π and π-π interactions. In vitro cytotoxicity of the complexes were assessed by MTT assay against four cancer cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and Ehrlich ascites carcinoma (EAC), and two normal cell lines namely normal human dermal fibroblasts (NHDF) and L6 myotubes with respect to the commercially used anticancer drug cisplatin. All the complexes induce apoptosis in EAC cells, which was confirmed by AO/EB, Hoechst 33258 and PI staining methods. The complexes block cell cycle progression of EAC cells in S phase (DNA synthesis). The cellular uptake studies confirmed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. In the in vivo anticancer studies, the complexes significantly reduce the tumour volume in female Swiss albino mice. Overall, our results ensure the role of thiosemicarbazone-based copper(i) complexes as prospective anticancer agents, induction of apoptosis and S phase arrest with the mitochondrial controlled pathway.

In vitro and in vivo anti-proliferative evaluation of bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors.

The bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal analysis, which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C-H···π inter and intramolecular interactions. The complex was found to be lipophilic as determined by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the commercially available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl-2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice. The bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway and significantly reduced the body weight and solid tumor volume in Swiss albino mice.

Heteroleptic silver(I) complexes with 2,2':6',2″-terpyridines and naproxen: DNA interaction, EGFR/VEGFR2 kinase, growth inhibition and cell cycle arrest studies.

A series of heteroleptic silver(I) complexes of the type [Ag(L1-3)(nap)] (1-3), where L1-3=4'-(4-substituted)-2,2':6',2″-terpyridines and nap=naproxen have been synthesized and characterized by elemental analysis and spectroscopic methods. The geometric parameters of the complexes were determined using UV-Vis and DFT calculations together with the IR spectral data. All the complexes adopted distorted tetrahedral geometry around silver(I) ion. The small HOMO-LUMO energy gap supports the bioefficacy of the complexes. DNA binding and melting experiments suggest the intercalative binding mode of the complexes to CT-DNA, which was further supported by molecular docking studies. The molecular docking studies of the heteroleptic silver(I) complexes with EGFR/VEGFR2 kinase receptors show hydrophobic, π-π, σ-π and hydrogen bonding interactions. All the complexes have been found to promote DNA cleavage through hydrolytic pathway. In vitro cytotoxicity activity of the complexes was tested against four human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and hepatoma (HepG2) cancerous, and one normal human dermal fibroblasts (NHDF) cell lines by MTT reduction assay. The morphological study by Hoechst 33258 staining revealed that the complex 3 induces apoptosis much more effectively than the other complexes. Further, all the complexes increases the DNA synthesis in S phase with the corresponding reduction in G0-G1 and G2/M phase, which suggest the growth inhibition mechanism on HepG2 cells was DNA damage mediated S phase arrest.

Targeting of DNA molecules, BSA/c-Met tyrosine kinase receptors and anti-proliferative activity of bis(terpyridine)copper(ii) complexes.

A series of homoleptic bis(terpyridine)copper(ii) complexes of the type [Cu(L(1-5))2]Cl2 (), where L(1-5) = 4'-(4-substituted)-2,2':6',2''-terpyridines, have been synthesized and characterized. The molecular structure of complex was confirmed by the single crystal XRD technique, and the geometry of the complexes is best described as distorted octahedral. Structural parameters from the crystallographic and DFT studies are in good agreement with each other. The small HOMO-LUMO energy gap supports bioefficacy of the complexes. DNA binding studies show high intrinsic binding constant values 1.53 ± 0.15, 1.62 ± 0.08 and 3.09 ± 0.12 × 10(5) M(-1) for complexes , and , respectively, with intercalative mode of binding to CT-DNA. The binding results were further supported by molecular docking studies. The experimental results indicate that the interaction between the complexes and BSA protein involves a static quenching mechanism. The molecular docking studies with c-Met tyrosine kinase receptors show hydrophobic and π-π interactions. All the complexes bring about hydroxyl radical mediated DNA cleavage in the presence of H2O2. In vitro cytotoxicities of the complexes () were tested against three cancerous cell lines, namely human breast adenocarcinoma (MCF-7), epithelioma (Hep-2) and cervical (HeLa) cell lines, and one non-tumorigenic human dermal fibroblast (NHDF) cell line by MTT reduction assay. The morphological assessment data obtained using Hoechst 33258 staining revealed that complex induces apoptosis much more effectively than the other complexes.