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A series of thiosemicarbazones and semicarbazone derivatives of (+/-)-3-menthone have been synthesized and their anti-HIV activity evaluated against HIV-1(III(B))and HIV-2 (ROD). The studies revealed that maximum protection is offered by chloro-substituted derivatives 2 and 7 against HIV-1 (III(B)) and HIV-2 (ROD).
The aim of this study was to investigate structural and biochemical changes in testes of rats treated with the thiosemicarbazone derivative thiazole ring Schiff base, (4-(1-phenyl-methylcyclobutane-3-yl)-2-(2-hydroxybenzylidene-hydrazino) thiazole (L), and its Cd(II) complex (CdL(2)). The animals were divided into three groups. Group I was designated as control. The rats in groups II and III were injected subcutaneously with L or CdL(2) respectively at 150-mg kg(-1) doses at 3-day intervals for 15 days. At the end of the study, blood samples were collected for biochemical analysis, and testes were removed for histological examinations. Serum levels of vitamin A, E and MDA of the L-injected group were similar to the control group. While CdL(2) treatment decreased serum vitamin A and E levels, it increased the MDA level compared to other groups. Histologically, the testes structures of L-treated animals were similar to the control. Spermatogenic cells in seminiferous tubules of CdL(2)-treated animals displayed necrosis. Nuclei of spermatogonia and primary spermatocytes were pyknotic and heterochromatic. Homogenous pink particles were present in place of the spermatids. The interstitial areas were oedematous and intertubular vessels were plugged. In conclusion, the present results indicate that L does not cause biochemical and morphological alterations, but its Cd(II) complex has degenerative effects in normal rat testes.
A series of indole-3-carboxaldehyde thiosemicarbazones with substituent variations at the 1 and 2 positions were prepared and evaluated for in vitro antiviral activity against vaccinia virus strain IHD and parainfluenza virus type 3, HA-I/CR-8 strain. The inhibitory activity of most compounds was restricted to the vaccinia virus, only compounds (III e) and (III f) being effective against both viruses. Structure-activity relationship are discussed.
Two novel series of arylidenepyruvic acid thiosemicarbazone and thiazoline derivatives were synthesized and evaluated as potential antimicrobial agents. These substances did not exhibit any significant antibacterial effects when tested against a variety of microorganisms.
The inhibitory effect of N,N'-bis(methylisatin-beta-thiosemicarbazone)-2-methylpiperazine (compound TSKI-VI) and methisazone (Marboran) on the growth of vaccinia virus (IHD strain) was studied in vitro and in vivo. The therapeutic indices of both compounds determined in vivo were similar, but TSKI-VI was found more efficient in vitro.
Dihydrofolate reductases (DHFR) of human, Candida albicans and E coli were docked with their original ligands of X-ray crystal complex using QXP (Quick eXPlore), a docking program. Conditions to reproduce the crystal structures within the root mean square deviation (rmsd) of 2.00 A were established. Applying these conditions, binding modes and species-specificities of a novel antibacterial compound, N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC), were studied. As the results, the docking program reproduced the crystal structures with average rmsd of six ligands as 0.91 A ranging from 0.49 to 1.45 A. The interactions including the numbers of hydrogen bonds and hydrophobic interactions were the same as the crystal structures and superposition of the crystal and docked structures almost coincided with each other. For AATSC, the results demonstrated that it could bind to either the substrate or coenzyme sites of DHFR in all three species with different degrees of affinity. It confirms the experimentally determined kinetic behavior of uncompetitive inhibition against either the inhibitor or the coenzyme. The docked AATSC overlapped well with the original ligands and major interactions were consistent with the ones in the crystal complexes. The information generated from this work should be useful for future development of antibacterial and antifungal agents.
PURPOSE: To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m(2) with escalation based on a modified Fibonacci scheme. PATIENTS AND METHODS: A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m(2) to 105 mg/m(2). Blood and urine samples were collected and 3-AP was measured by HPLC. RESULTS: A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade l occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease. CONCLUSIONS: Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m(2) on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.
PURPOSE: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer. STUDY DESIGN: 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m(2). Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m(2) in cohorts of three to six patients. Following the gemcitabine 1000 mg/m(2) dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m(2). RESULTS: 3-AP at 105 mg/m(2) administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m(2) produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m(2) administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis. CONCLUSIONS: 3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.
Copper(II) bis(thiosemicarbazone) complexes labelled with Cu-60/62/64 are useful radiopharmaceuticals for imaging blood flow and hypoxic tissues in vivo. The aim of this study was to identify structure-activity relationships within a series of analogues with different alkyl substitution patterns in the ligand, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Thirteen such complexes were synthesised and characterised spectroscopically and electrochemically. The uptake of each (labelled with Cu-64) in EMT6 tumour cells in vitro under normoxic and hypoxic conditions was studied. All complexes were taken up efficiently into cells, and some showed strong hypoxia selectivity, which was highly correlated with the Cu(II/I) redox potential. Redox potentials at the low end of the range were found to be essential for hypoxia selectivity. In turn, the redox potential was strongly correlated with alkyl substitution pattern, and the most important determinant of the redox potential was the number of alkyl groups on the diimine backbone of the ligand. Several complexes in the series warrant further evaluation as hypoxia imaging agents. The radioactivity uptake/release behaviour in the cells provides insight into possible mechanisms, and a model for hypoxia-selective intracellular trapping is discussed.
Kethoxal bis(thiosemicarbazone) induces the synthesis of four proteins (100 000, 70 000, 35 000 and 25 000 daltons) in normal chick embryo cells. The 70 000 dalton species is produced at the fastest rate 2 hr after exposure to the compound. Pulse-chase experiments revealed neither precursors nor products of these proteins and both actinomycin and cycloheximide inhibited their synthesis. Neither of the two substituents of the inducer, kethoxal or thiosemicarbazide, were active. The four proteins were induced in several other species, but human cells produced only three proteins (100 000, 70 000 and a different 30 000 dalton form).
A number of polyamine (PA) derivatives of thiosemicarbazone of 1,3-dichloroacetone (TDA) have been prepared and their effect on growth in vivo of tumorigenic but not metastatic cell strain (LY-R) of mouse lymphoma L5178Y has been investigated. Polyamine derivatives of TDA (PDT) were injected i.p. every third day (4 times, 10 or 25 mg/kg per injection) into DBA/2 mice inoculated i.p. or s.c. with LY-R cells. It has been found that disubstituted putrescine (Put), spermidine (Spd) and spermine (Spm) derivatives TDA exhibit a prometastatic activity as indicated by the appearance of solid tumor foci in subcutaneous tissues, liver and spleen. This activity depends mainly on the structure of the PA fragment and the presence of TDA. An increase in lipid bound sialic acid content after treating LY-R cells in vitro and in vivo with a Spm derivative has been found. These findings suggest that disubstituted PA derivatives of TDA and LY-R cells may be a useful model for investigation of the final steps in formation of metastases by lymphoma cells.
The influence of mefloquine and additional antimalarial drugs on (3H)adenosine uptake, macromolecular synthesis, and cell stability was determined in rodent red cells parasitized with Plasmodium berghei. High arylmethanol to cell ratios induced lysis, whereas inhibition of macromolecular synthesis occurred at lower drug/cell ratios. A 2-acetylpyridine thiosemicarbazone rapidly suppressed (3H)adenosine uptake, and also blocked macromolecular synthesis by parasitized cells.
Complexes of Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones), abbreviated as H2L, have been prepared and characterized by elemental analysis, molar conductance, magnetic moments (300-78 K) and spectral studies. On the basis of these studies, a distorted six-coordinate structure for Fe(L)Cl and a distorted five-coordinate structure for M(L) (M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), or Pt(II] are suggested. The ligands undergo deprotonation and appear to coordinate through the thione sulphur, the imine nitrogen and pyridyl nitrogen. All the ligands and metal complexes were screened for their antitumor activity against P 388 lymphocytic leukemia test system in mice, and it was found that a few of them possess significant activity at the dosages used.
The synthesis, spectroscopic studies, x-ray crystal structure, and biological properties of the complex [Cu(H2L)(OH2)Cl]Cl (1) (H2L = pyridoxal thiosemicarbazone) are reported. The compound crystallizes in space group P2(1)/n, a = 12.128(2), b = 9.096(2), c = 13.592(2) A, beta = 108.65(2) degrees, U = 1420.7 A3, and Z = 4. The molecular structure consists of discrete cations [Cu(H2L)(OH2)Cl]+ and Cl- anions. Each copper atom is in an approximately square pyramidal environment involving the phenolic oxygen, the imine nitrogen, the sulphur, and a water oxygen in the equatorial positions, while a chlorine atom occupies the axial position. The structure of this complex is compared to that of the dimeric [(Cu(HL)(OH2))2]Cl2.2H2O (2) obtained under different experimental conditions, to that of a Co(III) complex with the same ligand [Co(HL)L].4.5H2O (3) and to that of the free ligand H2L, especially in relation to its biological activity. Compounds 1 and 2 have not antiviral action in vitro with respect to RNA viruses, show an inductive effect on Friend erythroleukemia cells (FLC), erythroid differentiation and a suppressive effect regarding FLC proliferation. Complex 3 and the free ligand do not have biological activity.
Methyl 2-pyridyl ketone thiosemicarbazone (MPKT) was found to inhibit bovine herpesvirus-1 (BHV-1) at an ED50 concentration of approximately 5-10 microM. Several virus strains were shown to have similar sensitivity to the drug and serial passage of virus in the presence of MPKT failed to yield resistant progeny. There was evidence for toxic effects on cells at drug concentrations similar to those required to inhibit virus and passage of cells in low concentrations of MPKT gave results suggesting cumulative toxicity. Pre-incubation of cells in the presence of MPKT produced a residual antiviral effect. Taken together, these observations cast doubt on the selectivity of the drug for BHV-1, at least in the bovine system under test.
A series of 21 new 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones were synthesised by cyclisation of Mannich bases with thiosemicarbazides of variegated nature. The chemical structures of the compounds were proved by UV, IR, (1)H NMR, (13)C NMR spectroscopic data and elemental analyses. The antiamoebic activities of these compounds were evaluated by microdilution method against HM1:1MSS strain of Entamoeba histolytica. It was found that 3-chloro and 3-bromo substituents on the phenyl ring at position 3 of the pyrazoline ring enhanced the antiamoebic activity as compared to unsubstituted phenyl ring. Compounds 15, 17, 18, 20 and 21 showed less IC(50) value than metronidazole. Moreover, compound 21 have shown the most promising antiamoebic activity (IC(50)=0.6 microM vs IC(50)=1.8 microM of metronidazole).
A novel series of thiosemicarbazone and aminoacyl-thiazolidones derivatives were synthesized. Their structure suggests that these compounds could have anti-Trypanosoma cruzi activity. Biological evaluation indicates that some of these compounds are able to inhibit the growth of T. cruzi in concentrations non-cytotoxic to mammalian cells. Docking studies were carried out in order to investigate the binding pattern of these compounds for the T. cruzi cruzain (TCC) protein, and these showed a significant correlation with experimental data.
Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC50 of compound III-16 against SGC-7901 reaches to 0.032 microM.