- Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
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The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We determined that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar minimum inhibitory concentrations being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel antitubercular agents.
- Kesicki, Edward A.,Bailey, Mai A.,Ovechkina, Yulia,Early, Julie V.,Alling, Torey,Bowman, Julie,Zuniga, Edison S.,Dalai, Suryakanta,Kumar, Naresh,Masquelin, Thierry,Hipskind, Philip A.,Odingo, Joshua O.,Parish, Tanya
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- Small molecule quantification by liquid chromatography-mass spectrometry for metabolites of drugs and drug candidates
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Identification and quantification of the metabolites of drugs and drug candidates are routinely performed using liquid chromatography-mass spectrometry (LC-MS). The best practice is to generate a standard curve with the metabolite versus the internal standard. However, to avoid the difficulties in metabolite synthesis, standard curves are sometimes prepared using the substrate, assuming that the signal for substrate and the metabolite will be equivalent. We have tested the errors associated with this assumption using a series of very similar compounds that undergo common metabolic reactions using both conventional flow electrospray ionization LC-MS and low-flow captive spray ionization (CSI) LC-MS. The differences in standard curves for four different types of transformations (O-demethylation, N-demethylation, aromatic hydroxylation, and benzylic hydroxylation) are presented. The results demonstrate that the signals of the substrates compared with those of the metabolites are statistically different in 18 of the 20 substrate-metabolite combinations for both methods. The ratio of the slopes of the standard curves varied up to 4-fold but was slightly less for the CSI method. Copyright
- Dahal, Upendra P.,Jones, Jeffrey P.,Davis, John A.,Rock, Dan A.
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experimental part
p. 2355 - 2360
(2012/03/26)
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- PYRIMIDYLPYRROLE DERIVATIVES ACTIVE AS KINASE INHIBITORS
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Pyrimidylpyrrole derivatives of formula (1) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be
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Page/Page column 24
(2010/02/10)
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- Metal ion chelates of lipophilic alkyl diazinyl ketoximes as hydrolytic catalysts
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A series of lipophilic dodecyl hetaryl ketoximes (hetaryl = pyridin-2-yl, pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl as well as their methyl hetaryl homologues was synthesized and hydrolytic activity of their chelates with Co2+, Ni2+, Cu2+ and Zn2+ in a micellar matrix of hexadecyltrimethylammonium bromide or in homogeneous aqueous solutions was investigated using 4-nitrophenyl acetate, 4-nitrophenyl hexanoate and 4-nitrophenyl diphenyl phosphate as model substrates. While Co2+ and Cu2+ chelates are almost inactive, those of Ni2+ and Zn2+ exhibit considerable activity. None of the studied chelates promotes hydrolysis of the used phosphate. The effective species are chelates of the metal : ligand stoichiometry 1 : 3 and 1 : 1 with Ni2+ and Zn2+, respectively, when the ester cleavage proceeds in the micellar matrix. The 1 : 2 stoichiometry was found in aqueous solutions of Ni2+ and Zn2+ chelates of methyl ketoximes.
- Cibulka, Radek,Hampl, Frantisek,Martinu, Tomas,Mazac, Jiri,Totevova, Sonja,Liska, Frantisek
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p. 1159 - 1179
(2007/10/03)
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- Substituent Effects on Photochemical Hydrogen Abstraction in 2-Acylpyridines, 2-Acylpyrazines, and 4-Acylpyrimidines
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Stern-Volmer quenching of the photochemistry of 1c indicates that N- and O-abstraction (eqs 1 and 2, respectively) are quenched at different rates (Figure 1).For quenching of 2c kqτ is 157 M-1 and for 3c, 64 M-1.When 1c is sensitized with triplet sensitizers of increasing ET,N-abstraction increases (Table 1).These data indicate that N- and O-abstraction in 1c take place from distiguishable triplet states.Survey of Φp's of ring-substituted ketones 1b-d, 6d, 7a,b,d, 8b, 9b,d, 10b, and 11d demonstartes the effect of substitution on the competition between N- and O-abstraction (Table 2).For methyl- and dicyano-substituted ketones, the results can be understood simply in terms of shifts in ET of the n?* and ??* states of the heterocycle.The photochemistry of all these ketones requires consideration of interactions among three triplet states.
- Rao, C. Janakiram,Agosta, William C.
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p. 2125 - 2131
(2007/10/02)
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- Novel thiosemicarbazones derived from formyl- and acyldiazines: Synthesis, effects on cell proliferation, and synergism with antiviral agents
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The synthesis of a series of novel thiosemicarbazones (TSC's) derived from various alkyl diazinyl (3-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl) ketones and 3-pyridazinecarbaldehyde and their evaluation against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) as well as the determination of their cytotoxicity are described. In addition, the effects of combination of such TSC's with the well-known antiviral drugs acyclovir (ACV) and 3'-azido-3'-deoxythymidine (AZT) were studied. Under our experimental conditions, i.e. determination of virus-induced cytopathic effect upon infection of HUT78 cells with HSV-1 and upon infection of MT4 cells with HIV-1, no antiviral activity could be detected with any of the TSC's. However, pronounced effects on proliferation of these rapidly growing T4 lymphocyte cell lines were observed. Clear structure-activity relationships with regard to these cytotoxic effects could be established: compared to pyridine, pyrazine, or pyrimidine-derived TSC's most of the 3- pyridazinyl congeners investigated are less cytotoxic: introduction of a methyl group into C-6 of the pyridazine system or prolongation of the acyl moiety in these compounds has essentially no influence; all compounds bearing an N,N-dimethylamino or a cycloamino substituent are much more toxic than those with an NH2 or NHR substituent; the nature of R in the latter type of compounds has only moderate influence. It has been reported that combination of TSC's with the antiviral agent acyclovir (ACV) results in potentiation of this well-known drug. We evaluated the potential of our series of novel TSC's in combination with ACV for inhibition of HSV-1-induced cytopathic effect in HUT78 cells and in combination with 3'-azido-3'-deoxythymidine (AZT) for inhibition of HIV-1-induced cytopathic effect in MT4 cells. Only four compounds out of this series, all characterized by an unsubstituted NH2 group, exhibited moderate synergism with the above mentioned antiviral drugs. Our results do not support the previously expressed opinion that TSC's are selective antiviral agents. In our test systems no evidence for inhibition of virus-induced cytopathic effect was obtained. The TSC derivatives exhibited a broad range of cytotoxic effects, some at concentrations considerably below those reported to have antiviral efficacy. Several of our novel diazine- derived compounds proved advantageous over the previously described pyridine analogues with regard to cytotoxicity. Moderate synergism could be detected for relatively noncytotoxic TSC's with the antiviral drugs ACV (antiherpes) and AZT (anti-HIV).
- Easmon,Heinisch,Holzer,Rosenwirth
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p. 3288 - 3296
(2007/10/02)
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- ACIDIFYING EFFECTS OF AZA GROUPS IN THE NH ACIDITY OF AMINOAZINES AND THE CH ACIDITY OF ACETYLAZINES
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The pK values for a series of aminoazines and acetylazines containing one, two, or three aza groups in the ring were determined in dimethyl sulfoxide.There is a good linear correlation between pK values of the investigated NH and CH acids.The acidifying effects (ΔpK) of the aza groups at positions 2, 3, or 4 in relation to the side chain were determined and had values of 3.1, 2.4, and 4.5 logarithmic units in the aminoazines and 3.5, 2.9 and 4.8 logarithmic units respectively in the acetylazines.Except in the case of two ortho-located aza groups the effects are additive.Compared with dimethyl sulfoxide water has a differentiating effect on the acidity of the aminoazines, and this is explained by the formation of hydrogen bonds between the molecules of the proton-donating solvent and the aza groups of the anions of the aminoazines.
- Terekhova, M. I.,Petrov, E. S.,Mikhaleva, M. A.,Shkurko, O. P.,Mamaev, V. P.,Shatenshtein, A. I.
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- PYRIMIDINES. 73. SYNTHESIS OF ACETYLPYRIMIDINES
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It is shown that the use of benzene as the solvent in the preparation of 2- and 4-acetylpyrimidines from cyanopyrimidines via the Grignard reaction makes this reaction a practical method for the preparation of pyrimidinyl ketones.Preparatively convenient methods for the preparation of 4-acetylpyrimidine from 4-ethylpyrimidine through the α-oximino derivative and 5-acetylpyrimidine from 4,6-dichloro derivatives of pyrimidine are proposed.
- Naumenko, I. I.,Mikhaleva, M. A.,Mamaev, V. P.
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p. 710 - 714
(2007/10/02)
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- 2-Alkoxy(and 2-alkoxyalkyl)-2-heterocyclic-thioacetamides for inhibiting gastric acid secretion
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The compounds are 2-alkoxy(and 2-alkoxyalkyl)-2-heterocyclic-thioacetamides which are inhibitors of gastric acid secretion.
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- Pharmaceutical compositions and methods of inhibiting gastric acid secretion
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Pharmaceutical compositions and methods of inhibiting gastric acid secretion by administering N-aminomethyl heterocyclic thioacetamide compounds.
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- N-Aminomethyl heterocyclic thioacetamides
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N-Aminomethyl heterocyclic thioacetamide compounds are prepared by reacting a heterocyclic thioacetamide with formaldehyde and an amine. The products inhibit gastric acid secretion.
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