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[reaction: see text] The thiazole C-nucleoside analogue was synthesized by the Hantzsch cyclization method to form the thiazole ring and was then converted to the thiazole N-oxide C-nucleoside analogue by peracid oxidation of the heterocycle nitrogen. Incorporation of the thiazole and thiazole N-oxide phosphoramidites into DNA was successful though significant deoxygenation of the N-oxide occurred during DNA assembly. The mechanism proposed for the reduction of the thiazole N-oxide to thiazole involves the formation of an N-oxide phosphite ester.
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To estimate the influence of aryl group position on the immunostimulant properties of imidazo[2,1-b]thiazole derivatives, several compounds were obtained and tested, versus tetramisole hydrochloride, on the mobilisation of CD2 receptor by human T lymphocyte. The synthesis use the action of monobrominated beta-diketones on the 2-mercaptoimidazoline. So, 1-aryl-4-bromobutane-1,3-diones lead to 3-aroylmethyl-5,6-dihydroimidazo[2,1-b]thiazoles 4. Same, 1-aryl-2-bromobutane-1,3-diones and 1,3-diaryl-2-bromopentane-1,3-diones give respectively 3-aroyl-2-methyl-5,6-dihydroimidazo[2,1-b]thiazoles 5 and 3-aroyl-2-aryl-5,6-dihydroimidazo[2,1-b]thiazoles 6. Better yields are obtained when the reaction presents two steps. The first one, realized in acetone at room temperature, leads to an intermediate S-substituted 4,5-dihydroimidazole which, in second step, is cyclized in imidazo[2,1-b]thiazole compound via an unisolated carbinolamine. This one explains the univocal formation of 5 derivatives and the feasible blending in case of 6. The immunoactivity of several imidazothiazoles 4, 5 and 6 is lower that them of 6-aryl substituted compounds and particularly that the levamisole which is the reference product in this series.
Methyl 4-(isothiocyanatomethyl)thiazole-2-carbamate and methyl 4-(isothiocyanatomethyl)selenazole-2-carbamate have been prepared via chemical transformations involving 2-amino-4-(chloromethyl)thiazole (1) and 2-amino-4-(chloromethyl)selenazole (2), respectively, as starting materials. The homoanalog, methyl 4-(2-isothiocyanatoethyl)thiazole-2-carbamate, was prepared from (2-aminothiazol-4-yl)acetic acid. All compounds prepared were evaluated for their ability to inhibit leukemia L1210 cell proliferation. Methyl 4-(isothiocyanatomethyl)thiazole-2-carbamate (7) was the most active compound in this screen, inhibiting the growth of L1210 leukemic cells with an IC50 = 3.2 microM. Mitotic blocking appears to be its primary mechanism of cytotoxic activity. Compound 7 also was the only compound which demonstrated significant in vivo antifilarial activity against the adult worms of Acanthocheilonema viteae in experimentally infected jirds. This compound was inactive against Brugia pahangi at a dosage of 100 mg/kg x 5 days.
The synthesis of a series of 2-arylamido and 2-alkylamido derivatives of 2-amino-4-(isothiocyanatomethyl)thiazole and 2-amino-4-(isothiocyanatomethyl)selenazole is described. In vitro antiproliferative evaluations were carried out using L1210 cells. The 2-(alkylamido)thiazole derivatives were moderately antiproliferative, with IC50's of 4-8 microM. A significant increase in activity was obtained for the arylamido derivatives, with IC50's of 0.2-1 microM. The results obtained for the selenazoles were similar to those for the thiazoles. 2-Benzamido-4-(isothiocyanatomethyl)-thiazole (19) was found to be a potent inhibitor of GMP synthetase. None of the compounds prepared in this study demonstrated antifilarial activity.
A series of 5,6,6a,8,9,11a-hexahydroanaphth[1',2':4,5]imidazo[2,q-b]thiazoles (17 and 20) and 5,6,6a,9,10,11a-hexahydronaphth[2',1':4,5]imidazo[2,1-b]thiazoles has been synthesized with cis- and/or trans-1,2-diamino-1,2,3,4-tetrahydronaphthalenes as the key intermediates and subsequently evaluated for immunological activity (effects on antibody formation and delayed-type hypersensitivity reaction). Among the compounds tested trans-5,6,6a,8,9,11a-hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole (trans-17a) and (+/-)-5,6,6a beta,8,9,11a alpha-hexahydro-8 beta-hydroxy-9 beta-methyl-8 alpha-phenylnaphth[1',2':4,5]imidazo[2,1-b]thiazole (20a) showed the largest immunological activity in mice with a magnitude comparable to that of levamisole and were found to be considerably less toxic than levamisole in acute toxicological study. The structures of 18a and 20a were determined by X-ray crystallography.
The structural and dynamic aspects of the interaction of the thiazole containing lexitropsin (1) with an oligodeoxyribonucleotide were studied by high field 1H-NMR spectroscopy. Complete assignment of the 1H-NMR resonances of lexitropsin 1 was accomplished by 2D-NMR techniques. The complexation-induced chemical shifts and NOE cross peaks in the NOESY map of the 1:1 complex of lexitropsin (1) and d-[CGCAATTGCG]2 reveal that the thiazole ring of the lexitropsin (1) intercalates between dA4.A5 bases and the rest of the ligand resides in the minor groove of the AT rich core of decamer, thus occupying the 5'-AATT sequence on the DNA. Intercalation of the thiazole moiety of the drug has been detected by the presence of intermolecular NOEs both in the major and the minor groove of the decamer helix. The absence of intranucleotide NOEs between base protons and H1'/H2' protons suggested local unwinding of the binding site on the DNA. From COSY and NOESY methods of 2D-NMR, it was established that the N-formyl (amino) terminus of the thiazole lexitropsin (1) is projecting into the major groove towards A5H8 while the amidinium terminus lies in the minor groove towards the T7G8 base pairs of the opposite strand. The expected intranucleotide NOEs confirmed that the decadeoxyribonucleotide in the 1:1 complex exists in a right handed B-conformation. The presence of exchange signals along the binding site 5'-AATT indicated an exchange of the bound drug process wherein the rate of exchange between the two equivalent sites was estimated to be congruent to 130 s-1 at 30 degrees C and with delta G degrees of 62.4 kJ mol-1. Force field and Pi calculations permitted a rationalization of the experimentally observed binding mode in terms of preferred conformation of the ligand and repeat length in lexitropsins compared with the DNA receptor.
The geometries of the thiazole ring and the nitramino groups in N-(3H-thiazol-2-ylidene)nitramine, C3H3N3O2S, (I), and N-methyl-N-(thiazol-2-yl)nitramine, C4H5N3O2S, (II), are very similar. The nitramine group in (II) is planar and twisted along the C-N bond with respect to the thiazole ring. In both structures, the asymmetric unit includes two practically equal molecules. In (I), the molecules are arranged in layers connected to each other by N-H...N and much weaker C-H...O hydrogen bonds. In the crystal structure of (II), the molecules are arranged in layers bound to each other by both weak C-H...O hydrogen bonds and S...O dipolar interactions.
A series of 2-(5-nitro-2-thienyl)thiazoles and their vinylogs having substituted methylamine side chains has been prepared by halogen displacement on the corresponding 4-chloromethylthiazole. Of these, 4-morpholinomethyl-2-(5-nitro-2-thienyl)thiazole showed moderate activity against Trypanosoma cruzi and Trypanosoma rhodesiense in mice. This compound formed the lead for a series of analogous thiazole-4-carboxaldehyde hydrazones. Some of the latter were found active in curing murine Tryp. cruzi and Tryp. rhodesiense infections and to have low acute toxicity. A comparison with known active compounds is given and some structural features necessary for activity are discussed.
The homolytic arylation of thiazole with phenylazotriphenylmethane (as a free radical source) was carried out to explore the potential chemotherapeutic activity of the resulting triphenylmethyl derivatives. The experimental data differed from similar results on other isosteric heterocycles: one compound only was obtained, having both phenyl and triphenylmethyl groups in the heterocyclic nucleus. The structure of 2-phenyl-5-triphenylmethylthiazole was established by IR, 1H-NMR, and mass spectroscopy. In particular, the mass spectral investigation indicated the cleavage of the 2,3- and 4,5-ring bonds, in contrast with the usual behavior of other thiazole derivatives with no triphenylmethyl substituent.
Thiazole synthase (ThiG) catalyzes an Amadori-type rearrangement of 1-deoxy-d-xylulose-5-phosphate (DXP) via an imine intermediate. In support of this, we have demonstrated enzyme-catalyzed exchange of the C2 carbonyl of DXP. Borohydride reduction of the enzyme DXP imine followed by top-down mass spectrometric analysis localized the imine to lysine 96. On the basis of these observations, a new mechanism for the biosynthesis of the thiazole phosphate moiety of thiamin pyrophosphate in Bacillus subtilis is proposed. This mechanism involves the generation of a ketone at C3 of DXP by an Amadori-type rearrangement of the imine followed by nucleophillic addition of the sulfur carrier protein (ThiS-thiocarboxylate) to this carbonyl group.
The chemical synthesis of 4-(5-amino-2-furyl)thiazole (AFT) and its formation during the in vitro reductive metabolism of 4-(5-nitro-2-furyl)thiazole (NFT) by rat liver tissues on anaerobic incubation with NADPH were examined. AFT was synthesized by catalytic reduction of NFT with 5% palladium on activated carbon. Purified AFT, a pale yellow powder, melted at 105 degrees C and had an extinction coefficient of 16.3 mM-1 cm-1 at 297 nm in methanol. The proton n.m.r. spectrum, i.r. and mass spectra were consistent with the assigned structure. Analysis of the ethyl acetate extract, following incubation of NFT with rat liver tissue preparations, revealed a metabolite whose chromatographic and mass spectral characteristics were the same as those obtained with synthetic AFT, thus establishing the structural identity of the metabolite as AFT. These data show that AFT is formed on reduction and could act as a precursor for the formation of 1-(4-thiazolyl)-3-cyano-1-propanone as postulated earlier.
The title molecule, C(15)H(23)N(3)O(5)S, was prepared as a synthetic precursor to 4-methylthiazole-based DNA minor groove binders which would bear chiral amino acids in the sequence. The crystallographic evidence presented herein shows that the aromatic amide NH group preceding the thiazole ring points away from the direction of sulfur. The molecule is biplanar, with the dihedral angle between the N-terminus peptide moiety and the thiazole-containing plane being 49.7 (5) degrees, with a bend at the Calpha carbon.
The ionization constants of the following compounds have been determined spectrophotometrically in aqueous solution: [table: see text] The comparison of absorption spectra in UV and pK values of the compounds being described in this work and of the derivatives having a thiazole or thiazoline structure which were studied previously let us suggest that in aqueous solution for the III-H and IV-H neutral molecules and monoanions the thiazole is more probable.
The ionization constants of the following compounds have been determined spectrophotometrically in aqueous solution: [table: see text] The comparison of absorption spectra in UV and pK values of the compounds being described in this work and of the derivatives having a thiazole or thiazoline structure which were studied previously let us suggest that in the II-H neutral molecule and the I-H and II-H mono-anion the thiazole form prevails while in the case of the I-H neutral molecule the thiazoline form is more probable.
The synthesis of 2,3-dihydro-5-formylimidazo[2,1-b]thiazoles with different substituents at position 6 (CH3, C6H5, Cl, Br) is reported; thiosemicarbazones and tosylhydrazones were prepared from these aldehydes and from the 2,3-unsaturated analogues: these derivatives, submitted to a preliminary test, did not show significant antileukemic activity.
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