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[Resumen] El presente trabajo se centra en el estudio de la síntesis y caracterización estructural de nueve compuestos con potencial actividad fitosanitaria: cuatro ligandos, tres tiosemicarbazonas y una hidrazona, y sus respectivos complejos derivados de zinc(II). Las tiosemicarbazonas A, B y C se obtuvieron por condensación de 2- acetilpiridina con diferentes tiosemicarbazidas bajo calentamiento a reflujo en etanol y con catálisis ácida. De forma similar, la hidrazona D se sintetizó por reacción de 2- acetilpiridina y 2-cloro-6-hidrazinopiridina en etanol a temperatura ambiente y con catálisis ácida. El tratamiento de los ligandos A, B y D con cloruro de zinc mediante calentamiento a reflujo en etanol dio lugar a los compuestos de coordinación A1, B1 y D1. Del mismo modo, la reacción de los ligandos A y D con acetato de zinc dihidratado condujo a la formación de los complejos A2 y D2. En todos ellos, los ligandos tiosemicarbazona e hidrazona actúan como agentes quelatantes tridentados [N,N,S] y [N,N,N], respectivamente. Los compuestos obtenidos se caracterizaron mediante las técnicas de espectroscopía de RMN de 1H y 13C-{1H}, espectroscopía de IR y medidas de conductividad molar., [Resumo] O presente traballo céntrase no estudo da síntese e caracterización estrutural de nove compostos con potencial actividade fitosanitaria: catro ligandos, tres tiosemicarbazonas e unha hidrazona, e os seus respectivos complexos derivados de zinc(II). As tiosemicarbazonas A, B e C obtivéronse por condensación de 2-acetilpiridina con diferentes tiosemicarbazidas baixo quentamento a refluxo en etanol e con catálise ácida. De forma semellante, a hidrazona D sintetizouse por reacción de 2-acetilpiridina e 2-cloro-6-hidrazinopiridina en etanol a temperatura ambiente e con catálise ácida. O tratamento dos ligandos A, B e D con cloruro de zinc mediante quentamento a refluxo en etanol deu lugar aos compostos de coordinación A1, B1 e D1. Do mesmo xeito, a reacción dos ligandos A e D con acetato de zinc dihidratado conduciu á formación dos complexos A2 e D2. En todos eles, os ligandos tiosemicarbazona e hidrazona actúan como axentes quelatantes tridentados [N,N,S] e [N,N,N], respectivamente. Os compostos obtidos caracterizáronse mediante as técnicas de espectroscopía de RMN de 1H e 13C-{1H}, espectroscopía de IR e medidas de condutividade molar., [Abstract] The present study is dedicated to the synthesis and structural characterization of nine potential phytosanitary products: four ligands, three thiosemicarbazones and one hydrazone, and their respective complexes derived from zinc(II). Thiosemicarbazones A, B and C were obtained by condensation between 2- acetylpyridine and different thiosemicarbazides by heating under reflux in ethanol with acid catalysis. Similarly, hydrazone D was synthesized by reaction between 2- acetylpyridine and 2-chloro-6-hydrazinopyridine in ethanol at room temperature with acid catalysis. The treatment of ligands A, B and D with zinc chloride by heating under reflux in ethanol led to coordination compounds A1, B1 y D1. Likewise, reaction of ligands A and D with zinc acetate dihydrate led to the formation of complexes A2 and D2. In all these compounds, thiosemicarbazone and hydrazone ligands act as [N,N,S] and [N,N,N] tridentate chelating agents, respectively. The compounds obtained were characterized by 1H and 13C-{1H} NMR spectroscopy, IR spectroscopy and molar conductivity measurements.

In this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation.

In this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation.

In this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation.

In this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation.

[Resumen] El presente trabajo se centra en el estudio de la síntesis y caracterización estructural de nueve compuestos con potencial actividad fitosanitaria: cuatro ligandos, tres tiosemicarbazonas y una hidrazona, y sus respectivos complejos derivados de zinc(II). Las tiosemicarbazonas A, B y C se obtuvieron por condensación de 2- acetilpiridina con diferentes tiosemicarbazidas bajo calentamiento a reflujo en etanol y con catálisis ácida. De forma similar, la hidrazona D se sintetizó por reacción de 2- acetilpiridina y 2-cloro-6-hidrazinopiridina en etanol a temperatura ambiente y con catálisis ácida. El tratamiento de los ligandos A, B y D con cloruro de zinc mediante calentamiento a reflujo en etanol dio lugar a los compuestos de coordinación A1, B1 y D1. Del mismo modo, la reacción de los ligandos A y D con acetato de zinc dihidratado condujo a la formación de los complejos A2 y D2. En todos ellos, los ligandos tiosemicarbazona e hidrazona actúan como agentes quelatantes tridentados [N,N,S] y [N,N,N], respectivamente. Los compuestos obtenidos se caracterizaron mediante las técnicas de espectroscopía de RMN de 1H y 13C-{1H}, espectroscopía de IR y medidas de conductividad molar., [Resumo] O presente traballo céntrase no estudo da síntese e caracterización estrutural de nove compostos con potencial actividade fitosanitaria: catro ligandos, tres tiosemicarbazonas e unha hidrazona, e os seus respectivos complexos derivados de zinc(II). As tiosemicarbazonas A, B e C obtivéronse por condensación de 2-acetilpiridina con diferentes tiosemicarbazidas baixo quentamento a refluxo en etanol e con catálise ácida. De forma semellante, a hidrazona D sintetizouse por reacción de 2-acetilpiridina e 2-cloro-6-hidrazinopiridina en etanol a temperatura ambiente e con catálise ácida. O tratamento dos ligandos A, B e D con cloruro de zinc mediante quentamento a refluxo en etanol deu lugar aos compostos de coordinación A1, B1 e D1. Do mesmo xeito, a reacción dos ligandos A e D con acetato de zinc dihidratado conduciu á formación dos complexos A2 e D2. En todos eles, os ligandos tiosemicarbazona e hidrazona actúan como axentes quelatantes tridentados [N,N,S] e [N,N,N], respectivamente. Os compostos obtidos caracterizáronse mediante as técnicas de espectroscopía de RMN de 1H e 13C-{1H}, espectroscopía de IR e medidas de condutividade molar., [Abstract] The present study is dedicated to the synthesis and structural characterization of nine potential phytosanitary products: four ligands, three thiosemicarbazones and one hydrazone, and their respective complexes derived from zinc(II). Thiosemicarbazones A, B and C were obtained by condensation between 2- acetylpyridine and different thiosemicarbazides by heating under reflux in ethanol with acid catalysis. Similarly, hydrazone D was synthesized by reaction between 2- acetylpyridine and 2-chloro-6-hydrazinopyridine in ethanol at room temperature with acid catalysis. The treatment of ligands A, B and D with zinc chloride by heating under reflux in ethanol led to coordination compounds A1, B1 y D1. Likewise, reaction of ligands A and D with zinc acetate dihydrate led to the formation of complexes A2 and D2. In all these compounds, thiosemicarbazone and hydrazone ligands act as [N,N,S] and [N,N,N] tridentate chelating agents, respectively. The compounds obtained were characterized by 1H and 13C-{1H} NMR spectroscopy, IR spectroscopy and molar conductivity measurements.

In this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation.

Objectives Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead. Methods Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis. Results TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice. Conclusions TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted

Objectives Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead. Methods Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis. Results TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice. Conclusions TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted

Triapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP)2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV-Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro. The catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment.

The geometries, stabilities, and 1,3-dipolar cycloaddition reactivities of 24 mesoionic azomethine ylides and imines were investigated using density functional theory calculations at the M06-2X/6-311+G-(d,p)/M06-2X/6-31G-(d) level. The computed structures highlight how the commonly used "aromatic" resonance form should be replaced by two more accurate resonance structures. Stabilities of the dipoles were assessed by various homodesmotic schemes and are consistent with these compounds being nonaromatic. The activation free energies with ethylene or acetylene range from 11.8 to 36.6 kcal/mol. Within each dipole type, the predicted cycloaddition reactivities correlate with the reaction energies and the resonance stabilization energies provided by the various substituents. Endocyclic (X) heteroatoms increase the reactivity of the 1,3-dipoles in the order of O > NH ≅ S, whereas exocyclic (Y) substituents increase it in the order of CH2 > NH > O > S. Distortion/interaction analysis indicated that the difference in reactivity between differently substituted 1,3-dipoles is driven by distortion, whereas the difference between azomethine ylides and imines is related to lower interaction energies of imines with the dipolarophiles.

Thiosemicarbazones are well known compounds that show antitumoral and antibacterial proprieties[1] ; while crown ether moiety acts as ion sensor to entrap cations size-selectively from the environment, implied in the production of sensors, membrane ion transport or potential anti-cancerous species, among others[2]. The combination of both functions into the same molecule should increase their unique applications. Herein we report on the synthesis of a molecule that combines both functions. The main aspect is that the study has being performed beginning with the design of the compound using DFT calculations, with the package of programs g09[3], after which follows the final synthesis and characterization using 1H NMR, IR and crystallographic analysis

Thiosemicarbazones are formed by the condensation of an aldehyde or ketone with a thiosemicarbazide. They have high coordinative capacity given that they have several potential donor atoms through which they can bind to transition metals. This coordinative capacity can be increased if the R1 and R2 substituents include additional donor atoms. In addition, thiosemicarbazones as well as their semicarbazones analogues have considerable biological and pharmacological interest because of their antibacterial, antiviral and antitumor activity. This communication includes the preparation and characterization of a series of thiosemicarcarbazones and their applications in the synthesis of palladium organometallic compounds

Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.

The present work is carried out for the synthesis and evaluation of some new 1,3,4-thiadiazolines, 1,3-thiazolines and 1,3-thiazolidin-4-ones linked to 1,2,4-triazolo[1,5-a]benzimidazole as anti-inflammatory agents. Structure elucidation of these compounds was confirmed by IR, 1H-NMR, and mass spectrometry along with elemental microanalyses. All new compounds were tested for their anti-inflammatory activity in comparison to indomethacin (INM) where some of them showed promising results comparable to INM at 4 hours interval. The most active anti-inflammatory compounds (4b, 8c and 9a) were examined on gastric mucosa and didn’t show any gastric ulcerogenic effect compared with the reference INM. Moreover, LD50 of compounds (4b and 9a) were determined in mice; they were found non toxic up to 400 mg Kg–1 (i.p.). Also, docking simulation of some compounds into PLA2 active sites was studied.

Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.

The side effects of cisplatin such as toxicities are mainly due to the lack of selectivity of this chemotherapeutic agent. In order to increase selectivity of an anticancer agent, hormone molecule that targets a specific receptor may be utilized. The notorious side effects of cisplatin and the potential of hormone molecule have generated a research problem: can a cytotoxic compound with better selectivity and/or specificity made of ligand containing a hormone molecule be prepared? The aim of this study is to prepare cytotoxic nickel complexes containing Schiff base ligands of testosterone and thiosemicarbazide, which are selective towards cancerous cells. Besides, their ability as DNA binders and topoisomerase I inhibitors were tested as well. Three Schiff base ligands that are made of testosterone and three derivatives of thiosemicarbazide (TT, TE, and TP) and their nickel (II) complexes (NT, NE, and NP) were synthesized. Characterizations of these compounds were done by means of FTIR, CHN, 1H-NMR, and X-ray crystallography. Mononuclear complexes NT, NE, and NP adopt the distorted square planar geometry, with two molecules of Schiff base ligand were coordinated to nickel ion via two imine nitrogens and two tautomericthiol sulfurs. The cytotoxicity of these compounds against several cancerous cell lines (prostate cancer cells PC-3 and LNCaP, and colon cancer cell HCT 116) was investigated via MTT assay, with cisplatin as positive reference standard. Preferences towards different cancer cell lines were shown, where parent ligands and their nickel complexes favored different cells. For instance, nickel complex NT was shown to be active against PC-3 cells although its Schiff base ligand TT was unable to inhibit the growth of the same cell type. On the contrary, the inhibitory strength of both TE and TP against prostate cancer LNCaP was muted upon complexation with nickel ion. Apart from that, it is noteworthy that all compounds are less toxic towards human normal colon

The side effects of cisplatin such as toxicities are mainly due to the lack of selectivity of this chemotherapeutic agent. In order to increase selectivity of an anticancer agent, hormone molecule that targets a specific receptor may be utilized. The notorious side effects of cisplatin and the potential of hormone molecule have generated a research problem: can a cytotoxic compound with better selectivity and/or specificity made of ligand containing a hormone molecule be prepared? The aim of this study is to prepare cytotoxic nickel complexes containing Schiff base ligands of testosterone and thiosemicarbazide, which are selective towards cancerous cells. Besides, their ability as DNA binders and topoisomerase I inhibitors were tested as well. Three Schiff base ligands that are made of testosterone and three derivatives of thiosemicarbazide (TT, TE, and TP) and their nickel (II) complexes (NT, NE, and NP) were synthesized. Characterizations of these compounds were done by means of FTIR, CHN, 1H-NMR, and X-ray crystallography. Mononuclear complexes NT, NE, and NP adopt the distorted square planar geometry, with two molecules of Schiff base ligand were coordinated to nickel ion via two imine nitrogens and two tautomericthiol sulfurs. The cytotoxicity of these compounds against several cancerous cell lines (prostate cancer cells PC-3 and LNCaP, and colon cancer cell HCT 116) was investigated via MTT assay, with cisplatin as positive reference standard. Preferences towards different cancer cell lines were shown, where parent ligands and their nickel complexes favored different cells. For instance, nickel complex NT was shown to be active against PC-3 cells although its Schiff base ligand TT was unable to inhibit the growth of the same cell type. On the contrary, the inhibitory strength of both TE and TP against prostate cancer LNCaP was muted upon complexation with nickel ion. Apart from that, it is noteworthy that all compounds are less toxic towards human normal colon

Sposobnost rutenijum(II)–arenskih vrsta da koordinuju različite klase liganada, čini ihpogodnim za fino podešavanje hemijskih i farmaceutskih svojstava. Novosintetisanirutenijum(II)–arenski kompleksi dobijeni su u reakciji polaznog jedinjenja[RuCl2(η6–p–cimen)]2 sa odgovarajućim ligandom u 1 : 2 ili 1 : 2,2 molskom odnosu umetanolu, etanolu ili izopropanolu uz blago zagrevanje. Komercijalno dostupni ligandikorišćeni za pripremu kompleksa mogu se smatrati piridinskim derivatima sa acetilgrupama, amino i hlor supstituentima ili sa jednom ili dve karboksilne grupe. Drugagrupa liganada uključivala je kaprilni hidrazid (hidrazid sa dugim ugljovodoničnimlancem), hidrazid izonikotinske kiseline (hidrazid sa aromatičnim piridinskimprstenom), tiosemikarbazone i semikarbazone (dobijene u reakciji 3– i 4–acetilpiridinasa tiosemikarbazidom ili kaprilnim hidrazidom). Treća grupa liganada može se smatratiderivatima pikolinske kiseline sa fluor, hlor, brom ili metil supstituentima ilipripojenom fenil grupom dajući izohinolin–3–karboksilnu kiselinu. Sintetisanajedinjenja okarakterisana su elementalnom analizom, masenom spektrometrijom, IC iNMR spektroskopijama. Na osnovu dobijenih spektroskopskih podataka zaključeno jeda molekuli imaju takozvanu „three–leg piano–stool“ geometriju koja je uobičajena zaovaj tip jedinjenja, sa bidentatno ili monodentatno koordinovanim ligandima. Strukturerutenijum(II)–arenskih jedinjenja sa 3–acetilpiridinom, 2,4–piridindikarboksilnomkiselinom, 2,6–piridindikarboksilnom kiselinom, pikolinskom kiselinom, kaprilnimhidrazidom, 6–fluorpikolinskom i 6–brompikolinskom kiselinom potvrđene surendgenskom strukturnom analizom. Ispitivanjem citotoksične aktivnosti otkriven jeslab antiproliferativni efekat kompleksa na ispitivane tumorske ćelijske linije, saizuzetkom dva jedinjenja, prvog sa pikolinskom kiselinom i drugog sa izohinolin–3–karboksilnom kiselinom. Poslednje pomenuto jedinjenje pokazalo je značajno nižucitotoksičnu aktivnost prema normalnim ćelijama, Ability of ruthenium(II)–arene species to coordinate to different classes of ligands,makes them suitable for fine–tuning chemical and pharmaceutical properties. Novelsynthesized ruthenium(II)–arene complexes were obtained in the reaction of startingcompound [RuCl2(η6–p–cymene)]2 with the corresponding ligand in a 1 : 2 or 1 : 2.2molar ratio in methanol, ethanol or isopropanol with mild heating. Commerciallyavailable ligands used for preparation of complexes could be considered as pyridinederivatives with acetyl grups, amino and chloro substituents, or with one or twocarboxylic groups. Second group of ligands included caprylic hydrazide (hydrazide withlong hydrocarbon chain), isonicotinic acid hydrazide (hydrazide with aromatic pyridinering), thiosemicarbazones and semicarbazones (derived from reaction of 3– and4–acethylpyridine with thiosemicarbazide or caprylic hydrazide). Third group of ligandscould be considered as derivatives of picolinic acid with fluoro, chloro, bromo andmethyl substituents or fused phenyl group giving isoquinoline–3–carboxylic acid.Synthesized compounds were characterized by elemental analysis, mass spectrometry,IR and NMR spectroscopies. According to the obtained spectroscopic data themolecules adopt the usual „three–leg piano–stool“ geometry which is common for thistype of complexes, with ligands coordinated in a bidentate or monodentate manner. Thestructures of ruthenium(II)–arene compounds with coordinated 3–acetylpyridine, 2,4–pyridinedicarboxylic acid, 2,6–pyridinedicarboxylic acid, picolinic acid, caprylichydrazide, 6–fluoropicolinic acid and 6–bromopicolinic acid were determined by X–raycrystallography. Examination of the cytotoxic activity revealed low antiproliferativeeffect of complexes in investigated tumor cell lines, with exception of two compounds,the one with picolinic acid and the other with isoquinoline–3–carboxylic acid. Latercompound exhibited significantly lower cytotoxic activity in normal cells (MRC–5)against high activ

Sposobnost rutenijum(II)–arenskih vrsta da koordinuju različite klase liganada, čini ih pogodnim za fino podešavanje hemijskih i farmaceutskih svojstava. Novosintetisani rutenijum(II)–arenski kompleksi dobijeni su u reakciji polaznog jedinjenja [RuCl2(η6–p–cimen)]2 sa odgovarajućim ligandom u 1 : 2 ili 1 : 2,2 molskom odnosu u metanolu, etanolu ili izopropanolu uz blago zagrevanje. Komercijalno dostupni ligandi korišćeni za pripremu kompleksa mogu se smatrati piridinskim derivatima sa acetil grupama, amino i hlor supstituentima ili sa jednom ili dve karboksilne grupe. Druga grupa liganada uključivala je kaprilni hidrazid (hidrazid sa dugim ugljovodoničnim lancem), hidrazid izonikotinske kiseline (hidrazid sa aromatičnim piridinskim prstenom), tiosemikarbazone i semikarbazone (dobijene u reakciji 3– i 4–acetilpiridina sa tiosemikarbazidom ili kaprilnim hidrazidom). Treća grupa liganada može se smatrati derivatima pikolinske kiseline sa fluor, hlor, brom ili metil supstituentima ili pripojenom fenil grupom dajući izohinolin–3–karboksilnu kiselinu. Sintetisana jedinjenja okarakterisana su elementalnom analizom, masenom spektrometrijom, IC i NMR spektroskopijama. Na osnovu dobijenih spektroskopskih podataka zaključeno je da molekuli imaju takozvanu „three–leg piano–stool“ geometriju koja je uobičajena za ovaj tip jedinjenja, sa bidentatno ili monodentatno koordinovanim ligandima. Strukture rutenijum(II)–arenskih jedinjenja sa 3–acetilpiridinom, 2,4–piridindikarboksilnom kiselinom, 2,6–piridindikarboksilnom kiselinom, pikolinskom kiselinom, kaprilnim hidrazidom, 6–fluorpikolinskom i 6–brompikolinskom kiselinom potvrđene su rendgenskom strukturnom analizom. Ispitivanjem citotoksične aktivnosti otkriven je slab antiproliferativni efekat kompleksa na ispitivane tumorske ćelijske linije, sa izuzetkom dva jedinjenja, prvog sa pikolinskom kiselinom i drugog sa izohinolin–3– karboksilnom kiselinom. Poslednje pomenuto jedinjenje pokazalo je značajno nižu citotoksičnu aktivnost p, Ability of ruthenium(II)–arene species to coordinate to different classes of ligands, makes them suitable for fine–tuning chemical and pharmaceutical properties. Novel synthesized ruthenium(II)–arene complexes were obtained in the reaction of starting compound [RuCl2(η6–p–cymene)]2 with the corresponding ligand in a 1 : 2 or 1 : 2.2 molar ratio in methanol, ethanol or isopropanol with mild heating. Commercially available ligands used for preparation of complexes could be considered as pyridine derivatives with acetyl grups, amino and chloro substituents, or with one or two carboxylic groups. Second group of ligands included caprylic hydrazide (hydrazide with long hydrocarbon chain), isonicotinic acid hydrazide (hydrazide with aromatic pyridine ring), thiosemicarbazones and semicarbazones (derived from reaction of 3– and 4–acethylpyridine with thiosemicarbazide or caprylic hydrazide). Third group of ligands could be considered as derivatives of picolinic acid with fluoro, chloro, bromo and methyl substituents or fused phenyl group giving isoquinoline–3–carboxylic acid. Synthesized compounds were characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopies. According to the obtained spectroscopic data the molecules adopt the usual „three–leg piano–stool“ geometry which is common for this type of complexes, with ligands coordinated in a bidentate or monodentate manner. The structures of ruthenium(II)–arene compounds with coordinated 3–acetylpyridine, 2,4– pyridinedicarboxylic acid, 2,6–pyridinedicarboxylic acid, picolinic acid, caprylic hydrazide, 6–fluoropicolinic acid and 6–bromopicolinic acid were determined by X–ray crystallography. Examination of the cytotoxic activity revealed low antiproliferative effect of complexes in investigated tumor cell lines, with exception of two compounds, the one with picolinic acid and the other with isoquinoline–3–carboxylic acid. Later compound exhibited significantly lower cytotoxic activity in normal cells (M

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.

We have performed a combined computational and experimental study to elucidate the mechanism of a metal-free α-amination of secondary amines. Calculations predicted azaquinone methides and azomethine ylides as the reactive intermediates and showed that iminium ions are unlikely to participate in these transformations. These results were confirmed by experimental deuterium-labeling studies and the successful trapping of the postulated azomethine ylide and azaquinone methide intermediates. In addition, computed barrier heights for the rate-limiting step correlate qualitatively with experimental findings. © 2013 American Chemical Society.

This investigation is devoted to the synthesis of new representatives of 2-amino-5-imidazolil-1,3,4-thiadiazole systems, the study of some chemical transformations and the bactericidal activity. It has been shown that thiosemicarbazones obtained by condensation of 4-chloro-1H-5-formylimidazoles with thiosemicarbazide when heated with a triple surplus of iron (III) chloride hexahydrate in 80% acetate acid undergo oxidative cyclization with formation of new 2-amino-5-(4-chloroimidazole-5-yl)-1,3,4-thiadiazoles. The compounds synthesized are heterocyclic systems with two electrophilic centres that are widely used when obtaining biheterocyclic biologically active systems. While studying the chemical behaviour of 2-amino-1,3,4-thiadiazoles under research in reactions of annulation with series of bielectrophilic reagents it has been found that they do not react either with phenacylbromide or malononitrile, and with chloroacetylchloride the product of 5-aminoacylation is formed; it even when heated in the boiling DMF in the presence of K2CO3 is not prone to intramolecular cyclocondensation. At the same time heating of 2-amino-1,3,4-thiadiazoles with diethyl ether of acetylenedicarboxylic acid in the absolute boiling ethanol leads to formation of ethyl-7-oxo-[1,3,4]-thiadiazolo-[3,2-a]-pyrimidine-5-carboxylates. The results of studying the antibacterial properties of 2-amino-1,3,4-thiadiazoles have shown that the compounds synthesized possess a moderate bactericidal and fungicidal activity., Исследование посвящено синтезу новых представителей 2-амино-5-имидазолил-1,3,4-тиадиазольных систем, изучению некоторых их химических превращений и бактерицидной активности. Показано, что тиосемикарбазоны, полученные конденсацией 4-хлор-1Н-5-формилимидазолов с тиосемикарбазидом, при нагревании с 3-кратным избытком гексагидрата хлорида железа (III) в 80%-ной уксусной кислоте поддаются окислительной циклизации с образованием новых 2-амино-5-(4-хлоримидазол-5-ил)-1,3,4-тиадиазолов. Синтезированные соединения относятся к гетероциклическим системам с двумя электрофильными центрами, которые часто используются при получении бигетероциклических биологически активных систем. При изучении химического поведения исследуемых 2-амино-1,3,4-тиадиазолов в реакциях аннелирования с рядом биэлектрофильных реагентов обнаружено, что они не реагируют ни с фенацилбромидом, ни с малононитрилом, а с хлорацетилхлоридом образуется продукт 5-аминоацилирования, который даже при нагревании в кипящем ДМФА в присутствии K2CO3 не подвергается внутримолекулярной циклоконденсации. В то же время нагревание 2-амино-1,3,4-тиадиазолов с диэтиловым эфиром ацетилендикарбоновой кислоты в абсолютном кипящем этаноле приводит к образованию этил 7-оксо-[1,3,4]тиадиазол[3,2-а]пиримидин-5-карбоксилатов. Результаты изучения противомикробных свойств 2-амино-1,3,4-тиадиазолов показали, что синтезированные соединения обладают умеренной бактерицидной и фунгицидной активностью., Дослідження присвячене синтезу нових представників 2-аміно-5-імідазоліл-1,3,4-тіадіазольних систем, вивченню деяких їх хімічних перетворень та бактерицидної активності. Показано, що тіосемікарбазони, отримані конденсацією 4-хлоро-1Н-5-формілімідазолів із тіосемікарбазидом, при нагріванні з 3-кратним надлишком гексагідрату хлориду заліза(ІІІ) у 80%-ній оцтовій кислоті зазнають окиснювальної циклізації з утворенням нових 2-аміно-5-(4-хлороімідазол-5-іл)-1,3,4-тіадіазолів. Синтезовані сполуки відносяться до гетероциклічних систем з двома електрофільними центрами, що часто використовується при отриманні бігетероциклічних біологічно активних систем. При вивченні хімічної поведінки досліджуваних 2-аміно-1,3,4-тіадіазолів у реакціях анелювання з низкою біелектрофільних реагентів виявлено, що вони не реагують ні з фенацилбромідом, ні з малононітрилом, а з хлороацетилхлоридом утворюється продукт 5-аміноацилювання, який навіть при нагріванні в киплячому ДМФА в присутності K2CO3 не схильний до внутрішньомолекулярної циклоконденсації. В той же час нагрівання 2-аміно-1,3,4-тіадіазолів з діетиловим ефіром ацетилендикарбонової кислоти в абсолютному киплячому етанолі приводить до утворення етил 7-оксо-[1,3,4]тіадіазоло[3,2-а]піримідин-5-карбоксилатів. Результати вивчення антимікробних властивостей 2-аміно-1,3,4-тіадіазолів показали, що синтезовані сполуки виявляють помірну бактерицидну та фунгіцидну дію.

This research focuses on the synthesis of thiosemicarbazones [(1-aryl-5-formylimidazol-4-yl)thio]acetic acids and the study of some of their chemical transformations and biological activity. By condensation of [(1-aryl-5-formylimidazol-4-il)thio]acetic acids with thiosemicarbazide in boiling acetic acid the corresponding thiosemicarbazones have been obtained with high yields. They were used as effective N,S-binucleophiles in reactions of cyclocondensation with electrophilic reagents. In particular, heating of these thiosemicarbazones with monochloroacetic acid in the acetic acid medium results in formation of (1,3-thiazol-2-il)hydrazones [(1-aryl-5-formylimidazol-4-yl)thio]acetic acids. By the reaction of maleic anhydride with thiosemicarbazones of [(1-aryl-5-formylimidazol-4-il)thio]acetic acids in boiling dioxane 2-[(1H-imidazol-5-yl)methylenehydrazino)-4-oxo-1,3-thiazole-5-il]acetic acids have been synthesized. The compounds obtained show a moderate antioxidant effect. The maximum level of inhibition of free radical lipids oxidation in vitro is observed in final concentrations of 10-1M and is 31.94% compared to the control. The results of the bactericidal and fungicidal activity obtained show that the compounds studied are characterized by the moderate antimicrobial action: the minimal bacteriostatic and fungistatic concentrations are in the range of 62.5-2000 mcg/ml., Исследование посвящено синтезу тиосемикарбазонов [(1-арил-5-формилимидазол-4-ил)тио]уксусных кислот, изучению некоторых их химических превращений и биологической активности. Конденсацией [(1-арил-5-формилимидазол-4-ил)тио]уксусных кислот с тиосемикарбазидом в кипящей уксусной кислоте с высокими выходами получены соответствующие тиосемикарбазоны. Последние использованы как эффективные N,S-бинуклеофилы в реакциях циклоконденсации с электрофильными реагентами. В частности, их нагревание с монохлоруксусной кислотой в среде уксусной кислоты приводит к образованию (1,3-тиазол-2-ил)гидразонов [(1-арил-5-формилимидазол-4-ил)тио]уксусных кислот. Взаимодействием малеинового ангидрида с тиосемикарбазонами [(1-арил-5-формилимидазол-4-ил)тио]уксусных кислот в кипящем диоксане синтезированные 2-[(1Н-имидазол-5-ил)метиленгидразино)-4-оксо-1,3-тиазол-5-ил]уксусные кислоты. Полученные соединения проявляют умеренный антиоксидантный эффект. Максимальная степень торможения свободнорадикального окисления липидов in vitro отмечена в конечных концентрациях 10-1М и составляет 31,94% по сравнению с контролем. Полученные результаты бактерицидной и фунгицидной активности свидетельствуют о том, что исследуемые соединения характеризуются умеренным противомикробным действием: минимальная бактериостатическая и фунгистатическая концентрации находятся в диапазоне 62,5-2000 мкг/мл., Дослідження присвячено синтезу тіосемікарбазонів [(1-арил-5-формілімідазол-4-іл)тіо]оцтових кислот, вивченню деяких їх хімічних перетворень та біологічної активності. Конденсацією [(1-арил-5-формілімідазол-4-іл)тіо]оцтових кислот з тіосемікарбазидом у киплячій оцтовій кислоті з високими виходами отримані відповідні тіосемікарбазони. Останні використані як ефективні N,S-бінуклеофіли в реакціях циклоконденсації з електрофільними реагентами. Зокрема, їх нагрівання з монохлорооцтовою кислотою в середовищі оцтової кислоти приводить до утворення (1,3-тіазол-2-іл)гідразонів [(1-арил-5-формілімідазол-4-іл)тіо] оцтових кислот. Взаємодією малеїнового ангідриду з тіосемікарбазонами [(1-арил-5-формілімідазол-4-іл)тіо] оцтових кислот в киплячому діоксані синтезовані 2-[(1Н-імідазол-5-іл)метиленгідразино)-4-оксо-1,3-тіазол-5-іл]оцтові кислоти. Отримані сполуки виявляють помірний антиоксидантний ефект. Максимальний ступінь гальмування вільнорадикального окиснення ліпідів in vitro відзначено у кінцевих концентраціях 10-1М, який становить 31,94% у порівнянні з контролем. Отримані результати бактерицидної та фунгіцидної активності свідчать про те, що досліджувані сполуки характеризуються помірною антимікробною дією: мінімальна бактеріостатична та фунгістатична концентрації знаходяться в діапазоні 62,5-2000 мкг/мл.

Metal semicarbazone and thiosemicarbazone complexes have attracted much attention due to their diverse biological activities. Because of the ability of ruthenium(II)-arene species to coordinate to different classes of ligands, they are suitable for fine-tuning chemical and pharmaceutical properties. Ruthenium(II) arene-complexes containing different types of ligands: namely caprylic hydrazide (a hydrazide with a long hydrocarbon chain), isonicotinic acid hydrazide (a hydrazide with an aromatic pyridine ring), thiosemicarbazones and semicarbazones (derived from the reaction of 3- and 4-acetylpyridine with either thiosemicarbazide or caprylic hydrazide), were obtained in the reaction of [(eta(6)-p-cymene)RuCl2](2) with the corresponding ligands in a 1:2 or 1:2.2 molar ratio in methanol, ethanol or isopropanol with mild heating. The complexes were characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopies. The structure of complex 1 was determined by X-ray crystallography. Antiproliferative activity of the investigated complexes, determined for three human cancer cell lines (HeLa, A549 and LS-174) revealed moderate activity without significant influence on the matrix metalloproteinases (MMP-2 and MMP-9) activity.

OBJECTIVE: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans. SUBJECTS AND METHODS: To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. RESULTS: Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia. CONCLUSION: This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Metal semicarbazone and thiosemicarbazone complexes have attracted much attention due to their diverse biological activities. Because of the ability of ruthenium(II)-arene species to coordinate to different classes of ligands, they are suitable for fine-tuning chemical and pharmaceutical properties. Ruthenium(II) arene-complexes containing different types of ligands: namely caprylic hydrazide (a hydrazide with a long hydrocarbon chain), isonicotinic acid hydrazide (a hydrazide with an aromatic pyridine ring), thiosemicarbazones and semicarbazones (derived from the reaction of 3- and 4-acetylpyridine with either thiosemicarbazide or caprylic hydrazide), were obtained in the reaction of [(eta(6)-p-cymene)RuCl2](2) with the corresponding ligands in a 1:2 or 1:2.2 molar ratio in methanol, ethanol or isopropanol with mild heating. The complexes were characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopies. The structure of complex 1 was determined by X-ray crystallography. Antiproliferative activity of the investigated complexes, determined for three human cancer cell lines (HeLa, A549 and LS-174) revealed moderate activity without significant influence on the matrix metalloproteinases (MMP-2 and MMP-9) activity.

A family of heterocyclic thiosemicarbazone dyes (3a-f and 4) containing furyl groups was synthesized in good yields, characterized and their response in acetonitrile in the presence of selected anions was studied. Acetonitrile solutions of 3a-f and 4 showed absorption bands in the 335-396 nm range which are modulated by the electron donor or acceptor strength of the heterocyclic systems appended to the thiosemicarbazone moiety. Fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulphate, nitrate, acetate and cyanide anions were used in recognition studies. From these anions, only sensing features were seen for fluoride, cyanide, acetate and dihydrogen phosphate. Two clearly different chromo-fluorogenic behaviours were observed: (i) a small shift of the absorption band due to the coordination of the anions with the thiourea protons and (ii) the appearance of a new red shifted band due to deprotonation. For the latter effect, a change in the colour of solution from pale yellow to purple was observed. Fluorescence studies were also in agreement with the different effects observed in the UV/Vis titrations. In this case, hydrogen bonding interactions were visible through the enhancement of the emission band, whereas deprotonation induced the appearance of a new red-shifted emission. Logarithms of stability constants for the two processes (complex formation + deprotonation) for receptors 3a-f in the presence of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec V1.1.18 program. Semi-empirical calculations to evaluate the hydrogen-donating ability of the receptors and a prospective electrochemical characterization of compound 3b in the presence of fluoride were also performed. © 2012 The Royal Society of Chemistry.

A family of heterocyclic thiosemicarbazone dyes (3a-f and 4) containing furyl groups was synthesized in good yields, characterized and their response in acetonitrile in the presence of selected anions was studied. Acetonitrile solutions of 3a-f and 4 showed absorption bands in the 335-396 nm range which are modulated by the electron donor or acceptor strength of the heterocyclic systems appended to the thiosemicarbazone moiety. Fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulphate, nitrate, acetate and cyanide anions were used in recognition studies. From these anions, only sensing features were seen for fluoride, cyanide, acetate and dihydrogen phosphate. Two clearly different chromo-fluorogenic behaviours were observed: (i) a small shift of the absorption band due to the coordination of the anions with the thiourea protons and (ii) the appearance of a new red shifted band due to deprotonation. For the latter effect, a change in the colour of solution from pale yellow to purple was observed. Fluorescence studies were also in agreement with the different effects observed in the UV/Vis titrations. In this case, hydrogen bonding interactions were visible through the enhancement of the emission band, whereas deprotonation induced the appearance of a new red-shifted emission. Logarithms of stability constants for the two processes (complex formation + deprotonation) for receptors 3a-f in the presence of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec V1.1.18 program. Semi-empirical calculations to evaluate the hydrogen-donating ability of the receptors and a prospective electrochemical characterization of compound 3b in the presence of fluoride were also performed. © 2012 The Royal Society of Chemistry.

The aim of this study was to compare (64)Cu-diacetyl-bis(N(4)-methylsemicarbazone) ((64)Cu-ATSM) and (18)FDG PET uptake characteristics and (64)Cu-ATSM autoradiography to pimonidazole immunohistochemistry in spontaneous canine sarcomas and carcinomas.

To compare the distribution and uptake of the hypoxia tracer (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) PET/CT, FDG PET/CT and dynamic contrast enhanced perfusion CT (DCE-pCT) in spontaneous canine tumors. In addition (64)Cu-ATSM distribution over time was evaluated.

The aim of this study was to compare (64)Cu-diacetyl-bis(N(4)-methylsemicarbazone) ((64)Cu-ATSM) and (18)FDG PET uptake characteristics and (64)Cu-ATSM autoradiography to pimonidazole immunohistochemistry in spontaneous canine sarcomas and carcinomas.

To compare the distribution and uptake of the hypoxia tracer (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) PET/CT, FDG PET/CT and dynamic contrast enhanced perfusion CT (DCE-pCT) in spontaneous canine tumors. In addition (64)Cu-ATSM distribution over time was evaluated.

This work is focused on the synthesis and characterization of a series of N(4)- substituted thiosemicarbazones and the evaluation of their in-vitro anti-trypanosomal activity and toxicity. A series of thiosemicarbazones (1-4) and N(4)-phenyl-3-thiosemicarbazones (5-8) have been synthesized on R-(-)carvone, acetophenone, 4’-methylacetophenone and benzophenone by condensation reaction with good yields. All compounds were characterized by spectrometrical analysis methods infrared IR, nuclear magnetic resonance NMR (1H &13C) and mass spectrometry MS, confirming their structures respectively, and were evaluated for their invitro parasitic activity against the bloodstream form of the strain 427 of Trypanosoma brucei brucei using the “LILIT, Alamar Blue” method (Baltzet al., 1985; Hirumi et al., 1994; Räz et al.,1997). Their toxicity against brine shrimp larvae (Artemia salina Leach) was studied, according to the method of Michael et al. (1956) resumed byVanhaecke et al. (1981) and bySleet and Brendel (1983). Some of them have exhibited a strong trypanocidal activity, especially compounds 8, 3, 1 and 4 with their half-inhibitory concentrations (IC50) values equal to 8.48, 8.73, 39.71 and 67.17 micro-molar (µM) respectively. Except compounds 1 and 4whose half-lethal concentration (LC50) values were20.58 and 33.72 µM respectively and then toxics, all synthesized compounds showed negligible toxicity against Artemia salinaL. (LC50> 280 µM) and good selectivity (S) (SI “index” =1).

The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or - prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid), 5-substituted 2'-deoxyuridines (i.e., idoxuridine), IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir) and alkoxyalkyl prodrugs thereof (such as CMX001), viral egress inhibitors (such as tecovirimat), and cellular kinase inhibitors (such as imatinib).

10-Oxo-4,6,7,8,9,10-hexahydroprazolo[1,5-a][1]benzothieno[2,3-d]pyrimidine-3-carbaldehyde (2) was prepared by Vilsmeier-Haack reaction of 3-amino-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (1). Reaction of carbaldehyde derivative 2 with malononitrile afforded arylidene malononitrile 3. Cyclization of the latter compound with thiourea yielded pyrimidinethione 4. Interaction of carbaldehyde derivative 2 in presence of thiourea with keto- compounds such as ethyl acetoacetate, or acetylacetone, or dimedone or ethyl cyanoacetate gave pyrimidine derivatives 5-8. Hydrazinolysis of carbaldehyde derivative 2 gave the hydrazone 9. Reaction of the latter with phenyl isothiocyanate afforded thiosemicarbazone 10, which underwent cyclization with oxalyl chloride to give thioxoimidazolidinedione 11. Condensation of compound 2 with thiosemicarbazide furnished thiosemicarbazone derivative 12. Reaction of compound 2 with aminopyrazolone in the presence of an acid and/or a base afforded pyrazolones 13 and 14. Treatment of carbaldehyde derivative 2 with cyanoacetohydrazide gave acrylohydrazide 15. Interaction of the latter with carbon disulfide yielded mercaptooxadiazole 16. Condensation of compound 2 with acetylpyridazinone 17 produced chalcone 18. Reaction of  compound 18 with malononitrile in pyridine gave cyanopyran 19, while its reaction with malononitrile in presence of ammonium acetate in ethanol yielded cyanopyridine 20. Structures of the newly synthesized products have been deduced on the basis of elemental analysis and spectral data. The synthesized compounds were screened for their antimicrobial activity.Â

10-Oxo-4,6,7,8,9,10-hexahydroprazolo[1,5-a][1]benzothieno[2,3-d]pyrimidine-3-carbaldehyde (2) was prepared by Vilsmeier-Haack reaction of 3-amino-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (1). Reaction of carbaldehyde derivative 2 with malononitrile afforded arylidene malononitrile 3. Cyclization of the latter compound with thiourea yielded pyrimidinethione 4. Interaction of carbaldehyde derivative 2 in presence of thiourea with keto- compounds such as ethyl acetoacetate, or acetylacetone, or dimedone or ethyl cyanoacetate gave pyrimidine derivatives 5-8. Hydrazinolysis of carbaldehyde derivative 2 gave the hydrazone 9. Reaction of the latter with phenyl isothiocyanate afforded thiosemicarbazone 10, which underwent cyclization with oxalyl chloride to give thioxoimidazolidinedione 11. Condensation of compound 2 with thiosemicarbazide furnished thiosemicarbazone derivative 12. Reaction of compound 2 with aminopyrazolone in the presence of an acid and/or a base afforded pyrazolones 13 and 14. Treatment of carbaldehyde derivative 2 with cyanoacetohydrazide gave acrylohydrazide 15. Interaction of the latter with carbon disulfide yielded mercaptooxadiazole 16. Condensation of compound 2 with acetylpyridazinone 17 produced chalcone 18. Reaction of  compound 18 with malononitrile in pyridine gave cyanopyran 19, while its reaction with malononitrile in presence of ammonium acetate in ethanol yielded cyanopyridine 20. Structures of the newly synthesized products have been deduced on the basis of elemental analysis and spectral data. The synthesized compounds were screened for their antimicrobial activity.Â

Patients and methods: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m(2), daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of > 3 months; one prior chemotherapy regimen was allowed. Results: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. Conclusions: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

The coordination behaviour of a new thiosemicarbazone Schiff-base building block incorporating a bulky tosyl group, towards different metal ions has been investigated by means of an electrochemical preparative procedure. The lead(II) complex shows an intense fluorescence emission with a quantum yield of 0.13. In the case of the silver complex, it has a stoichiometry of [Ag2(L1)]2·3H2O. During reactions with manganese and copper metals, interesting catalysed processes were found to take place, with remarkable consequences regarding the ligand skeleton structure. In synthesising the manganese complex, we obtained an unexpected dithiolate thiosemicarbazone tosyl ligand, H2L2, as a side-product, which has been fully characterised including by X-ray diffraction analysis. In the case of copper, its crystallised product shows the copper atoms coordinated to a new cyclised thiosemicarbazone ligand, H2L3. The zinc complex [Zn(L1)]4 (12) displays a particular tetranuclear zeolite-type structure capable of hosting small molecules or ions, presumably through hydrogen bonding.

The reaction of,tin(TV) tetrachloride with 3-formylpyridine semicarbazone and different 3-formylpyridine thiosemicarbazones produces [Sn(HL)CL3][SnCl5] where HL stands for the neutral ligand. The tin(IV) complexes were characterized using a variety of spectroscopic techniques. Coordination through the pyridine nitrogen occurs in all cases. Solvation studies in DMSO indicated that dissociation of the ligands and their complete replacement by solvent molecules occurs.

The antimycobacterial activity of 21 thiosemicarbazone compounds on growth of strains of M. intracellulare was determined. The minimal inhibitory concentration for 5 of the compounds against strains growing in 7H9 broth was 1 mcg/m1 or less. One of these compounds, compound H, was chosen for further study and its effectiveness for treating M. intracellulare infected Swiss-Webster mice was determined. The drug was remarkably effective in eliminating organisms from the spleens and lungs of mice that had been infected by either intravenous or intraperitoneal injections of M. intracellulare serotype 12 (Trudeau D-673).

Experimental antimalarial drugs were assessed for their blood schizontocidal activity in the Aotus trivirgatus - Plasmodium falciparum - P. vivax model. WR 242511 and WR 238605, both 8-aminoquinolines, cured blood-induced P. vivax infections, when administered at doses of 1.0 and 4.0 mg base per kg (x 3 days), respectively. Both drugs cured P. falciparum infections, but at doses greater than required for cure of P. vivax blood infections. Two thiosemicarbazones, WR 231010 and WR 235591, were ineffective against infections of the Uganda Palo Alto and Vietnam Smith strains of P. falciparum. WR 24696, an indolquinoline, had minimal activity against parasites of the Uganda Palo Alto strain and no activity against infections of the Vietnam Smith strain of P. falciparum. Assessment of two acridinols, in progress, indicated that one, WR 250547, cleared parasitemias of the chloroquine-resistant Vietnam Smith strain when administered at doses of 1.0, 4.0, or 16.0 mg base per kg (x 3 days).

This invention relates to various 2-acetyl- and 2-propionylpyridine thiosemicarbazones which are substituted on the 4-nitrogen atom. These compounds are useful in the treatment of gonorrhea and, in addition, many are useful either in the treatment of malaria or bacterial infection. Also disclosed are several synthetic procedures used to prepare the thiosemicarbazones., Supersedes PAT-APPL-311 368-81.

This invention relates to various 2-acetyl- and 2-propionylpyridine thiosemicarbazones which are substituted on the 4-nitrogen atom. These compounds are useful in either in the treatment of malaria or bacterial infection. Also disclosed are several synthetic procedures used to prepare the thiosemicarbazones. (Author), Supersedes PAT-APPL-311 369-81.

This invention relates to various 2-acetyl- and 2-propionylpyridine thiosemicarbazones which are substituted on the 4-nitrogen atom. These compounds are useful in the treatment of gonorrhea and, in addition, many are useful in the treatment of malaria or bacterial infection. Also disclosed are several synthetic procedures used to prepare the thiosemicarbazones., Supersedes PAT-APPL-004 247-79.

This invention relates to various 2-acetyl- and 2-propionylpyridine thiosemicarbazones which are substituted on the 4-nitrogen atom. These compounds are useful in the treatment of gonorrhea and, in addition, many are useful either in the treatment of malaria or bacterial infection. Also disclosed are several synthetic procedures used to prepare the thiosemicarbazones. (Author), Supersedes PAT-APPL-311 370-81.

N-methyl isatin-beta-thiosemicarbazone, a known inhibitor of pox-virus in vitro and in vivo, is without effect upon the virulent bacteriophage T4, T4B, T4Bo1, or the temperate phage lambda grown in E. coli. At concentrations which show striking anti-viral activity against the pox-virus in tissue culture, this compound exhibits no activity in the processes of adsorption, penetration, or replication of the bacteriophage studied. (Author)

Antiviral chemotherapy resides in the research of chemical products capable of modifying, with a given mechanism, the complex series of events which accompany, in the nucleous of the cell and of the nucleous of the whole animal, the development of the viral infection. This is a question of the adsorption of the virus on the cell, of its multiplication, of its liberation, of its propagation from one cell to the next or the lesions and the symptoms which this infection causes directly or indirectly. Antiviral chemotherapy, in contrast to antibacterial chemotherapy has as its essential objective not only the infectious particle itself but also the association virus-cell, the viral infection being only an alteration of the normal cell function by the introduction of a strange genetic material capable of deflecting for its own benefit certain synthetic activities of the cell. The antiviral classification is based essentially on the chemical nature and the probable chemical activity of the products considered. (Author), Trans. of Actualities Pharmacologiques (France) n21 p133-174 1963.