Synthesis, antibacterial and cytotoxic activity evaluation of hydroxyurea derivatives

Synthesis and biological evaluation for a series (N = 16) of cyclic and acyclic hydroxyurea derivatives including benzotriazole-, isocyanuirc acid- and biuret-containing compounds, are disclosed. 1-N-(benzyloxycarbamoyl)benzotriazole was used as benzyloxyisocyanate donor, a useful intermediate in the preparation of substituted hydroxyurea. Antibacterial activities of synthesized hydroxyurea derivatives were tested on three E. coli strains, i.e., strain susceptible to antibiotics, strain resistant to macrolide antibiotics and strain resistant to aminoglycoside antibiotics. Six compounds (three acyclic and three cyclic hydroxyureas) showed the growth inhibition of tested E. coli strains, with different specificity toward each strain. Results of the cytotoxic activity evaluation revealed that twelve out of sixteen test compounds were cytotoxic to human acute monocytic leukemia THP-1 and/or on human acute T cell leukemia Jurkat cell line. 1-(N-hydroxycarbamoyl)benzotriazole (5) increased metabolic activity of both cell lines. Two compounds, 1-(N-hydroxycarbamoyl)benzotriazole (5) and N,N’,N’’-trihydroxybiuret (15) were identified as potential NO donors

Kinetics and Mechanism of Oxidation of Hydroxyurea with Hexacyanoferrate(III) Ions in Aqueous Solution

Hydroxyurea (HU) effectively reduces Fe(CN)63− to Fe(CN)6 4− species in neutral and basic aqueous solution via an electron transfer process that includes the formation and subsequent fading out of a free radical, U•(U• ≡ H2N−C(=O)N(H)O•). The EPR spectrum of U• in H2O solutions suggests that the unpaired electron is located predominantly on the hydroxamate hydroxyl-oxygen atom. Visible spectrophotometric data reveal HU as a two-electron donor. Stoichiometry of the studied reaction can be formulated as: 2Fe(CN)63− + NH2CONHOH + ½H2O → 2Fe(CN)64− + CO2 + NH3 + ½N2O + 2H+. Lack of evidence for the formation of NO probably is a consequence of fast dimerization of HNO in comparison with the rate of its oxidation, which is slow due to the low reduction potential of the Fe(CN)63−/ Fe(CN)64− couple.The kinetic of oxidation of HU by Fe(CN)63− was studied using stopped-flow technique, as a function of H+, HU, Fe(CN)63− and Fe(CN)64− concentrations, as well as a function of ionic strength and temperature. The kinetic results reveal that oxidation of HU by Fe(CN)63− proceed via an outer-sphere electron-transfer process. The effect of ionic strength on the reaction rate reveals that NaFe(CN)62− is the reacting species rather than Fe(CN)63− ion. The rate of the redox process was found to be first order with respect to both redox reactants while the H+ concentration dependence make clear that U− is about four orders of magnitude more reactive than HU. The formal reduction potentials for U•/U− and HU•/HU couples were estimated from the kinetic results as +0.47 V and +0.84 V, respectively.</p

Siderophore chemistry of vanadium. Interaction between vanadium(V) and desferrioxamine B in aqueous acidie perchlorate solution

Complexation of vanadium(V) at 25°C in 2 M NaCI04/HCI04' by desferrioxamine B chelator results in the formation of 1: 1 complex when concentration of HCI04 in the reaction mixture is higher than 0.1 M. The apparent equilibrium constant and the second order rate formation 'constant in 0.5 M HCI04 are: Kapp = (6 ± 2) X 106 M-l, k = (2.3± 0.2)X 105 M-l S-l,respectively

Aspartamide polyhydroxamic acids - synthesis and iron(III) complexes

Several linear and cross-linked poly[a,P-C/V-hydroxy-D,L-aspartamide)] derivatives (polyhydroxamic acids) were synthesized by aminolysis of poly-D,L-(2,5-dioxo-l,3-pyrrolidinediyl) (polysuccinimide; PSI) with the corresponding hydroxylamines. Aminolysis of the succin- imide (SI) units in PSI with hydroxylamine or IV-methylhydroxy- lamine was either complete or only partial, depending on the molar ratio of the Si-units and the hydroxylamine. Copolymers with partially opened SI rings were subjected to further aminolysis by 2-ami- noethanol, di(2-hydroxyethyl)amine, butylamine, 2-phenylethy- lamine, 1,2-diaminoethane, and 1,6-diaminohexane. Use of diamines led to cross-linked polymers. Polyhydroxamic acids differed in the average relative molecular mass, the number and spacing between the hydroxamic acid groups and in their solubility. The polyhydroxamic acids formed colored complexes with the iron(III) ions. Stability constants for the iron(III)-poly[a,P-(N-hydroxy)-D,L- aspartamide] complexes were determined by spectrophotometric titration. Values of the equilibrium quotients at 25 °C were calculated and confirmed to be: Qj = (1.0 ± 0.4) x 102, Q% = (1.3 ± 0.7) x 10~2

Kinetics and mechanism of interactions between iron(lll) and desferrioxamine B. The formation and hydrolysis of ferrioxamine B in acidic aqueous solution

The kinetics of the formation and hydrolysis of ferrioxamine B complexes have been studied in acidic aqueous solution (0.001- -1.0 M HCl) at 25.0 °c, μ = 1.0 M (maintained by NaCl). Two stage kinetics have been observed in both the formation and in the hydrolysis reactions. The proposed reaction model involves formation/ hydrolysis of bidentate, tetradentate, and hexadentate bonded desferrioxamine B to iron(III). The formation of the bidentate complex occurs by two paths: one involving unhydrolysed ferric ion yields the rate constant k1 = 282 M-1 s-1, and the other via hydrolysed ferric species gives the rate constant k1' = 4.1 X 103· M-1 s-1• The analogous rate constants for the reverse hydrolysis reactions were obtained; k - 1 = = 0.65 M-1 s-1 for the acid dependent and k _ 1' = 0.016 s·1 for the acid independent path. The formation and hydrolysis rate constants of the tetradentate linked complex have been calculated using the steady-state approximation as k 2 = 9 s·1 and k _2 = 2 M-1 s-1, respectively. The conversion of tetradentate to hexadentate as well as hydrolysis of the hexadentate to tetradentate bonded species have been characterized by the rate constants k 3 = 2.2 s-1 and k _ 3 = = 18 M-1 s-1, respectively. These results are compared with kinetic data previously reported. Chloride media increases the rate of formation and hydrolysis of the bidentate species, and possibly has the same effect on the tetradentate species but does not affect hydrolysis of the hexadentate complex. These effects were analyzed in terms of a labilization of iron(III) coordinated ligands by inner-sphere coordinated chloride

Kinetic and equilibrium thermodynamic description of the interaction of desferrioxamine B and acethydroxamic acid with iron(III) in acid aqueous perchlorate

Same activation parameters of the stepwise formation and hydrolysis of the iron(III) complexes with desferrioxamine B and acethydroxamic acid, as well as the enthalpy and entropy of the overall reactions are reported. The mechanism of the formation and hydrolysis of the iron-(III)-hydroxamate complexes is disscused in view of the obtained data

Equilibrium studies on complexation of iron (III) by acet-, glycinium and betaine hydroxamic acids

EquHtbri1um studies were performed to invest:iga.te ithe com- 1plexa1tion of aqueous high-spin irnn(!I!) by three synthetic monohydroxamic actds: acet-, glycin.ium, and be1ta1ne hydroxamic acids. Under neutral and acidic conditions studied, 1acethydroxamic acid is neutral (AH), while glycinium CGH2+) a.nd betaine CBH+) hydroxa.mic ac1ds have a positive charge on ·the nitro:gen atom. The equilibrium quotients ·for the formation of monoacethydroxamatoiron( I!!) complex Qi', A-= [FeA2+J/( [Fe3+] [A- J ), bisacethydroxamatoiroin(III) complex Q2', A-= [FeA2+J/( [Fe3+] [A-]2), a.nd .tirisacethydroxamatoiiron(!I!) comp;lex Q3', A-= = [FeA3]/([Fe3+J [A-]3) were found to be: lg Qi', A-= 10.38 (0.01), lg Q2', A-= 19.16 (0.14), and lg Q3', A- = 25.56 (0.70). Ana.logous equiUbrimn quotients for glycinium-hydrnxamic acid with protonated amino group (GH2+) and betaine-hydroxamic ac·id CBH+) ligands are: lg Qi', GH = [Fe(GH)3+J/([Fe3+J [GHJ) = 7.77 (0.08), lg Q2', GH = [Fe(GH)i3+J/([Fe3+J [GHJ2) = 13.71 (0.08), lg QJ', GH = [Fe.CGH)J3+]/([Fe3+J [GHJ3) = 17.63 (0.14), lgQi',B = [FeB3+]/([Fe3+) [BJ)= 7.28 (0.02), lgQ2',B = [FeB23+J/([Fe3+] [B]2) = 13.41 (0.05), and lgQ3'.B = [FeB33+]/([Fe3+) [B]3) = 16.46 (0.24). Determinations were made at 1.0 M ionic strength (NaCD and at 25 °C by spectrophotometric methods. The synthesis of a new compound beatine hydroxamic acid chloride i1s desc·ri:bed. INTRODUCTIO

Complexation of iron(III) by cystinedihydroxamic acid

In acidic and neutral solutions, cystinedihydroxamic acid (H2L2+) binds ferric ion forming monomeric and dimeric complexes of 1:1, 2:2 and 2:3 metal to ligand stoichiometry. Comparison of the obtained equilibrium and spectral data for mono(cystinedihydroxamato) iron(III) with those of other hydroxamatoiron(III) complexes suggests the same mode of coordination. The Fe2L3 complex has been isolated and characterized by elemental analysis and IR spectra

Kinetics of the formation and hydrolysis of (desferrioxamine B) aluminium (III) and gallium(lII) complexes in acidic aqueous perchlorate solutions

The kinetics of complexation of desferrioxamine B with M (M = Al(III) and Ga(III) in acidic aqueous perchlorate solutions at 25 °C and 2 M ionic strength are reported. The pseudo-first order complex formation and hydrolysis reactions were followed spectrophotometrically in the UV region. For both metals, a parallel-path mechanism, in which the M(H2Ü)|+ and M(H20)5(OH)2+ ions react with the fully protonated ligand (H4dfb+) to form M(H20)4(H3dfb)3+ complexes, is operative. The calculated formation rate constants for unhydrolyzed and hydrolyzed Al(III) ions are 0.0211(17) s_1 M*1 and 189(3) s-1 M_1, whereas for Ga(III) are 5.45(77) s-1 M-1 and 2.15(3) • 104 s-1 M-1, respectively. For the reaction of H4dfb+ with the unhydrolyzed Al(III) and Ga(III) ions, enthalpies and entropies of activation are: 97.6 ± 8.2 kJ mol-1, 52.5 ± 2.9 J K-1 mol-1, and 87.2 ± 7.2 kJ mol'1, 71.3 ± 2.9 J K_1 mol-1, respectively. The results are discussed in terms of a model in which the loss of the first water molecule coordinated to the metal ions is the rate determining step. The obtained ca. 104 times higher reactivities of the hydrolyzed than the unhydrolyzed metal ions are consistent with the dissociative (Eigen) mechanism