Synthesis and structure of new bicopper(II) complexes bridged by N-(2- aminopropyl)-N'-(2-oxidophenyl)oxamide: the effects of terminal ligands on structures, anticancer activities and DNA-binding properties

A novel dissymmetrical N,N′-bis(substituted)oxamide ligand, N-(2-aminopropyl)-N′-(2-oxido- phenyl)oxamide (H₃apopoxd) (L), and its three bicopper(II) complexes, [Cu₂(apopoxd)(bpy)]- (ClO₄)·H₂O (1), [Cu₂(apopoxd)(dabt)](ClO₄)·2H₂O (2), and [Cu₂(apopoxd)(phen)₂](ClO₄) (3) (bpy = 2,2′-bipyridine; dabt = 2,2′-diamino-4,4′-bithiazole; phen = 1,10-phenanthroline) have been synthesized and characterized. The crystal structures of the three bicopper(II) complexes have been determined by X-ray single-crystal diffraction. In complexes 1 and 2, the cis-apopoxd³⁻ ligands bridge two copper(II) ions in square-planar geometries with the corresponding separations of 5.1868(3) and 5.2016(4) Å, respectively. While in complex 3, the apopoxd³⁻ ligand adopting a trans conformation bridges the two copper(II) ions in distorted square-pyramid environments with a Cu···Cu distance of 5.2508(7) Å. The anticancer activities and DNA-binding properties of L and the three complexes were investigated.     

Synthesis, characterization and anticancer studies of mixed ligand dithiocarbamate palladium(II) complexes

Six mixed ligand dithiocarbamate Pd(II) complexes (1-6) of general formula [(DT)Pd(PR₃)Cl], where DT = dimethyldithiocarbamate (1, 5), diethyldithiocarbamate (2, 3), dicyclohexyldithiocarbamate (4), bis(2-methoxyethyl)dithiocarbamate (6); PR₃ = benzyldiphenylphosphine (1), diphenyl-2-methoxyphenylphosphine (2), diphenyl-p-tolylphosphine (3), diphenyl-m-tolylphosphine (4), tricyclohexylphosphine (5), diphenyl-2-pyridylphosphine (6) have been synthesized and characterised using Elemental analysis, FT-IR, Raman and multinuclear magnetic resonance (NMR) spectroscopy. Compounds 1 and 2 were also characterized by single crystal X-ray diffraction technique (XRD). The XRD study reveals that the Pd(II) moiety has a pseudo square-planar geometry, in which two positions are occupied by the dithiocarbamate ligand in a bidentate fashion, while at the remaining two positions organophosphine and chloride are present. The anticancer activity of the synthesized metallodrugs was checked against DU145 human prostate carcinoma (HTB-81) cells, the IC₅₀ values indicate that the compounds are highly active against these cells. These Pd(II) complexes also show moderate antibacterial activity against gram positive and gram negative bacteria.     

Synthesis, crystal structures, and biological evaluation of manganese(II) and nickel(II) complexes of 4-cyclohexyl-1-(1-(pyrazin-2-yl)ethylidene)thiosemicarbazide

4-Cyclohexyl-1-(1-(pyrazin-2-yl)ethylidene)thiosemicarbazide (HL) and its transition metal complexes formulated as [Mn(L)₂] (1) and [Ni(L)₂] (2) have been prepared in 55-75% yield and characterized by elemental analysis, IR, MS, NMR and single-crystal X-ray diffraction studies. Biological activities of the synthesized compounds have been evaluated against selected Gram positive bacteria Bacillus subtilis, Gram negative bacteria Pseudomonas aeruginosa and the K562 leukemia cell line, respectively. The cytotoxicity data suggest that these compounds may be endowed with important biological properties, especially the nickel complex 2 with MIC = 31.2 μg/mL and IC₅₀ = 0.53 μM, respectively. Effect of the free ligand and its two complexes on Mitochondria membrane potential (MMP) and PI-associated fluorescence intensity as well as their effect on cell apoptosis in K562 leukemia cell line was also studied. The tested compounds may exert their cytotoxicity activity via induced loss of MMP.     

Pyridine-derived thiosemicarbazones and their tin(IV) complexes with antifungal activity against Candida spp

[(n-Bu)Sn(2Ac4oClPh)Cl₂] (1), [(n-Bu)Sn(2Ac4oFPh)Cl₂] (2), [(n-Bu)Sn(2Ac4oNO₂Ph)Cl₂] (3), [(n-Bu)Sn(2Bz4oClPh)Cl₂] (4), [(n-Bu)Sn(2Bz4oFPh)Cl₂] (5) and [(n-Bu)Sn(2Bz4oNO₂Ph)Cl₂] (6) were obtained by reacting [(n-Bu)SnCl₃] with 2-acetylpyridine-N(4)-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N(4)-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N(4)-orthonitrophenyl thiosemicarbazone (H2Ac4oNO₂Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO₂Ph). The antifungal activity of the studied compounds was evaluated against several Candida species.Upon coordination of H2Bz4oNO₂Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO₂Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.     

Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones

A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (3a-g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8-methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8-bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC₅₀ values lower than 5 μg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control.     

Ruthenium(II) phosphine/diimine/picolinate complexes: inorganic compounds as agents against tuberculosis

This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2′-bipyridine (bipy), 4,4′-dimethyl-2,2′-bipyridine (Me-bipy), 4,4′-dichloro-2,2′-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF₆ (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF₆ (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF₆ (SCAR03) and [Ru(pic)(dppb)(phen)]PF₆ (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)₂]PF₆ (SCAR05) and cis-[RuCl₂(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds.     

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4′,3′:-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4′,3′:1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3′,2′:1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD₅₀ values in the low micromolar to nanomolar concentration range.     

Anomalous behavior of pentacoordinate copper complexes of dimethylphenanthroline and derivatives of terpyridine ligands: Studies on DNA binding, cleavage and apoptotic activity

Copper(II) complexes with substituted terpyridine ligands, namely [Cu(itpy)(dmp)](NO₃)₂ (1) and [Cu(ptpy)(dmp)](NO₃)₂ (2) have been synthesized and characterized. The interaction of the complexes with CT-DNA has been explored using spectroscopic techniques and viscosity. Complexes 1 and 2 bind in the grooves of DNA, interestingly 1 in the minor and 2 in the major groove. Both the complexes have been found to promote DNA cleavage; complex 1 through hydrolytic and 2 oxidative. Complexes 1 and 2 have been found to be cytotoxic and bring about apoptosis of human lung cancer cell line A549.     

Transition metal complexes of 2, 6-di ((phenazonyl-4-imino) methyl)-4-methylphenol: structure and biological evaluation

A symmetric ligand 2, 6-di ((phenazonyl-4-imino)methyl)-4-methylphenol (Dpmp) and its cobalt dinuclear complex (Co₂(Dpmp)₂(NO3)₂(H₂O)₂·NO3·EtOH, (1) and zinc mononuclear complex Zn(Dpmp)(NO₃)₂, (2) have been prepared. The crystal structures were determined by single-crystal X-ray diffraction. The biological activity has been evaluated by examining their anti-oxidative activity and ability to bind to bovine serum albumin (BSA) and calf-thymus DNA (CT DNA) with UV-vis absorption, fluorescence, viscosity measurements and circular dichroism (CD) spectroscopies. The complexes exhibit good binding propensity to BSA and CT DNA. Both 1 and 2 have been found to promote cleavage of pUC19 DNA in the absence of any reducing agent. Antioxidant tests in vitro show the compounds possess significant antioxidant activity against superoxide and hydroxyl radicals.     

Synthesis, structural characterization and biological studies of the triphenyltin(IV) complex with 2-thiobarbituric acid

The reaction between 2-thiobarbituric acid (H₂TBA), which was treated with an equimolar amount of potassium hydroxide, in a water with triphenytin chloride in methanol, results in the formation of the {[Ph₃Sn(O-HTBA)]}_n (1) complex. Crystals of the hydrated 1 with formula {[Ph₃Sn(O-HTBA)]·0.7(H₂O)}_n were growth from methanol/acetonitrile solution, of the white precipitation, filtered off, from the reaction. The crystal structure of complex 1 has been determined by X-ray diffraction at 120 K. Complex 1 is polymeric. The geometry around the tin(IV) ions is trigonal bi-pyramidal with coordination to three C atoms from phenyl groups and one O atom from a de-protonated HTBA ligand.Complex 1 and the already known [(n-Bu)₃Sn(O-HTBA)·H₂O] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (cervical), OAW-42 (ovarian), MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (renal) and additionally, the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line MTSV17 with a Trypan Blue assay. Moreover complex 1 was evaluated for its in vitro cell growth proliferation activity against leiomyosarcoma cells (LMS), MCF-7 and MRC-5 cells with a Thiazolyl Blue Tetrazolium Bromide (MTT) assay. The type of cell death caused by complexes 1 and 2 was also evaluated by use of flow cytometry assay. The results showed that these compounds mediate a strong cytotoxic response to normal and cancer cell lines tested through apoptosis and induce cell cycle arrest in S phase of the cell cycle, suggesting DNA intercalation (direct or indirect) with the complexes. Finally, the influence of these complexes 1 and 2 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied.     

Synthesis, cellular uptake, apopotosis, cytotoxicity, cell cycle arrest, interaction with DNA and antioxidant activity of ruthenium(II) complexes

A new ligand and two ruthenium(II) complexes [Ru(bpy)₂(DNPIP)](ClO₄)₂1 and [Ru(bpy)₂(DAPIP)](ClO₄)₂2 were synthesized and characterized. The DNA-binding constants for complexes 1 and 2 were determined to be 2.24 (±0.30) × 10⁵ M⁻¹ (s = 1.29) and 6.34 (±0.32) × 10⁴ M⁻¹ (s = 2.84). The photocleavage of pBR322 DNA by Ru(II) complexes was investigated. The cytotoxicity of complexes 1 and 2 were assessed against three tumor cell lines. The apoptosis and cellular uptake were studied. The retardation assay of pGL 3 plasmid DNA was explored. The cell cycle arrest was analysized by flow cytometry. The antioxidant activities of the ligand and complexes were also investigated.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3

A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT_1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT_1A and SERT with K_i ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT_1A presynaptic receptors in the inducible hypothermia test in mice.     

Synthesis and crystal structure of two new dinuclear cobalt(II) complexes interaction with HeLa cells

Two novel dinuclear complexes [Co₂(L)₂(phen)₂·2H₂O]_n (1), [Co₂(L)₂(bipy)₂]_n (2) (where phen = 1,10-phenanthroline, bipy = 2,2′-bipyridine, and L = biphenyl-2,4′-dicarboxylic acid) have been synthesized and characterized using IR, ¹H NMR, element analysis and single-crystal X-ray diffractometry. The binding of the complexes with HC-DNA (HeLa cells DNA, which was extracted by ourselves) was investigated by fluorescence spectrum. The experimental results show that the two complexes have the ability to bind with extracted HC-DNA. Gel electrophoresis assay demonstrates the ability of the complexes to cleave the extracted HC-DNA. The complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. Further more, the apoptotic tests indicate that the complexes have an apoptotic effect on HeLa cells.     

Preparation and pharmacological evaluation of a novel series of 2-(phenylthio)benzo[b]thiophenes as selective MT2 receptor ligands

A series of N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)acylamides was synthesized and evaluated for binding affinity and intrinsic activity at melatonin receptors. The affinity of each compound for the melatonin receptors was determined by binding studies on cloned human MT₁ and MT₂ receptors expressed in CHO cells. Agonist and antagonist potency was measured on the [³⁵S]GTPγS binding assay for the most interesting compounds. The new derivatives 8-14 showed modest to high selectivity (between 4 and 220) for MT₂ receptors. The most selective compound, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)but-3-enamide (14), an MT₂ ligand with affinity for the MT₂ receptor similar to that of melatonin and a 220-fold preference over MT₁ receptors, acts as a partial agonist. In addition, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)propionamide (9), a nanomolar MT₂ ligand with a good selectivity ratio (MT₁/MT₂ = 51) shows antagonist activity on both melatonin receptors.     

Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands

A novel class of imidazo[1,2-a]pyridines as melatonin receptor ligands is designed and synthesized. The affinities of 3-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-N-methyl-propionamide 8, N-[2-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-ethyl]-acetamide 13 and N-(1-hydroxy-3-(5-methoxy-2-phenyl-1H-indol-3-yl)propan-2-yl)acetamide 18 are evaluated for binding on melatonin receptors. Compound 8 present good selectivity for MT₂ over MT₁ (MT₁/MT₂ = 19) and compound 13 have good affinities for both MT₁ (Ki :28 nM) and MT₂ (Ki : 8 nM).     

Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines

Synthesis of a new series of diarylureas and diarylamides having 1H-pyrrolo[3,2-c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2-c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives (8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a-e showed the highest potency against A375P with IC₅₀ in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC₅₀ in micromolar range. Compounds 8b, 8g, 9b-d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI.     

Influence of chirality of V(V) Schiff base complexes on DNA, BSA binding and cleavage activity

New chiral V(V) Schiff base complexes (S)-[VO(OMe)L] and (R)-[VO(OMe)L] were synthesized and characterized by microanalysis, infrared (IR), UV-Visible, Circular dichroism (CD) spectroscopy and single crystal X-ray studies. The interaction of these complexes with calf thymus (CT) DNA and bovine serum albumin (BSA) protein showed chiral expression DNA/protein binding strength. The influence of chirality was also observed in cytotoxicity assay of Hep 2 cells. (R)-[VO(OMe)L] enantiomer exhibited higher binding constant (5 ± 1 × 10⁵ M⁻¹) as compared to (S)-[VO(OMe)L] (8 ± 1 × 10⁴ M⁻¹). The fluorescence quenching, thermal melting and viscosity data suggest DNA surface and/or groove binding nature of the complexes and electrophoresis studies also showed greater activity for (R)-[VO(OMe)L] in cleaving DNA and protein as against (S)-[VO(OMe)L].     

Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists

The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases’; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K⁺-induced calcium signals in bovine chromaffin cells.     

One-pot microwave assisted synthesis under green chemistry conditions, antioxidant screening, and cytotoxicity assessments of benzimidazole Schiff bases and pyrimido[1,2-a]benzimidazol-3(4H)-ones

The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals have been unambiguously achieved based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) ¹³C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively.     

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode.