Vol. 15 No. 3(59) (2017)
The aim of this review was to summarize and systematize literature on chemistry of alkenylsubstituted imidazoles known as important synthetic substrates and precursors for the synthesis of biologically active substances. Two approaches to the synthesis of these compounds are reviewed: 1) the imidazole ring formation based on functionalized alkenyl compounds; 2) functionalization of imidazole derivatives with the alkenyl moiety. The second approach prevails and includes condensation of methylimidazoles with carbonyl compounds, reactions of formylimidazoles with compounds containing activated methylene groups and phosphorus ylides, as well as reactions of dehydration and dehydrohalogenation of substituted imidazoles. The methods of synthesis of alkenylsubstituted imidazoles have been analyzed in detail; their synthetic potential and limits have been described. Special attention is paid to the authors’ own research on the synthesis of new 4-chloro-5-alkenylsubstituted imidazoles using 5-formylimidazoles as precursors. Analysis of the chemical properties of alkenylsubstituted imidazoles has allowed conducting their strict classification and systematizing their typical transformations. Reactions of cyclocondensation are the first ones to be mentioned, they proceed through the interaction of the alkenyl moiety with another functional group or endocyclic Nitrogen. Other transformations such as heterocyclofunctionalization, oxidation and reduction are based on transformation of the alkenyl moiety. It should be noted that heterocyclization processes are new for chemistry of alkenylimidazoles, they are successfully applied to 5-(2-nitro-alkenyl)- and 5-(2-arylvinyl)substituted derivatives, and due to them it is possible to obtain new promising hybrid structures.
The synthesis and study of vasoactive properties of new 4-functionalized 1,3-oxazoles containing the N-methyl-D-glucamine fragment in position 5
The analysis of literature data shows the prospects of searching drugs with different biological activity among 1,3-oxazoles.
Aim. To develop preparative methods of the synthesis of new 4-fuctionalized 1,3-oxazoles containing the N-methyl-D-glucamine fragment in position 5 and to study their physical, chemical and biological properties.
Results and discussion. It has been found that 1,3-oxazoles reveal the vasodilatative and vasoconstrictive effect on the tonic activity of the vessels preactivated with phenylephrine depending on the concentration and the chemical structure of the compounds. The article describes the vasodilatative and vasoconstrictive efficacy of new 1,3-oxazoles compared to the known adrenolytic drug – amiodarone, and the inhibitor of potassium channels – 4-aminopyridine (pimadin).
Experimental part. A number of new 4-fuctionalized 1,3-oxazoles containing the N-methyl-D-glucamine fragment in position 5 was synthesized. Their biological activity was assessed under the action of selective agonists of 1-adrenoreceptors (phenylephrine), 5HT2A-receptor (serotonin) on the isolated segments of the rat’s aorta previously constricted or by blocking potassium channels with the high potassium Krebs solution.
Conclusions. It has been found that in the case of the serotonin constricted isolated aortic segments only the vasoconstriction is observed in contrast of the vessel activated with phenylephrine. If the constriction of the aortic segments is carried out with a high potassium solution, there is no vasotonic activity of 1,3-oxazole derivatives. The data obtained indicate the possible molecular mechanism of their biological activity with the participation of vascular adrenergic receptors and potassium channels, their inhibition may lead to vasodilatation at the comparatively high concentration of the compounds or vasoconstriction at the comparatively low concentration of oxazoles, respectively.
The effect of the structure of 5-(benzylthio)isoxazoles on selectivity of the synthesis of 5-(chlorosulfonyl)isoxazoles has been determined. The chemical behavior in relation to amines has been described.
Aim. To develop the methods for the synthesis of 5-(chlorosulfonyl)- isoxazoles and 4-chloro-5-(chlorosulfonyl)isoxazoles as promising reagents for construction of prospective bioactive compounds.
Results and discussion. The number of 5-(benzylthio)isoxazoles was obtained by cyclocondensation of N-hydroxyimidoyl chlorides or 2-chloro-2-(hydroxyimino) acetates with benzylethynylsulfide. Their oxidative chlorination with gaseous chlorine led to formation of the mixture of isoxazole-5-sulfonyl chlorides and 4-chloroisoxazole-5-sulfonyl chlorides. The ratio between these products in the mixture depended on the nature of the substitution group in position 3 of the isoxazole ring. For the synthesis of 4-chloro-5-(chlorosulfonyl)isoxazoles with acceptable yields the approach of an advance chlorination of 5-benzylthioisoxazoles by N-chlorosuccinimide with further oxidative chlorination was used.
Experimental part. The synthesis of the starting and target compounds was performed in classic preparative conditions; flesh-chromatography; elemental analysis; LCMS; 1H and 13C NMR-spectroscopy were used.
Conclusions. The reaction of oxidative chlorination of 5-(benzylthio)-3-isoxazoles has been studied. The synthetic approach for the previously unknown representatives of isoxazole-5-sulfonylchlorides has been developed.
The synthesis, physico-chemical properties, the antibacterial and antifungal activity of 2-[(5-(adamantane-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]acetohydrazide ylidene derivatives
One of the main stages for creating a drug is the synthesis of a promising substance. The combination of adamantane and 1,2,4-triazole in one molecule provides the fertile ground for the synthesis of new compounds with low toxicity and a pronounced pharmacological activity.
Aim. To synthesize 2-[(5-(adamantane-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]acetohydrazide ylidene derivatives, study their physico-chemical properties, the antimicrobial and antifungal activity.
Results and discussion. During the synthetic part of our work the aldehyde selection was based on the presence of various substitutes in the aromatic or heterocyclic nuclei. Benzaldehyde and its fluorine-, bromine-, hydroxy-, nitro-, methoxy-, dimethylamino- and dimethoxy- substituents were used. Furan-2-carbaldehyde, 5-nitrofuran-2-carbaldehyde, pyridine-2-ylcarbaldehyde and pyridine-3-ylcarbaldehyde were used among heterocyclic aldehydes. The structure of the synthesized compounds was confirmed by modern complex physico-chemical methods of analysis, elemental analysis, IR, NMR 1H-spectroscopy, and their individuality was proven by HPLC-MS. In the course of the initial screening of the antimicrobial activity of the ylidene derivatives of 2-[(5-(adamantane-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]acetohydrazide synthesized it was found that the compounds obtained revealed a moderate antimicrobial and antifungal activity.
Experimental part. Ylidene derivatives of 2-[(5-(adamantane-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]acetohydrazide were obtained by the reaction of nucleophilic addition of the hydrazide fragment of the aldehyde group carbonyl. The antimicrobial and antifungal activities were determined by serial two-fold dilution in the liquid nutrient media. To compare the antimicrobial activity of the compounds studied trimethoprim was used as a reference drug.
Conclusions. New ylidene derivatives of 2-[(5-(adamantane-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]acetohydrazide have been synthesized; their structure has been determined by modern physico-chemical methods of analysis (elemental analysis, IR- and NMR 1H-spectroscopy), and their individuality has been confirmed by HPLC-MS. Among the compounds synthesized the substances with the antimicrobial and antifungal action that is similar or in some cases even exceed the action of the reference drug trimethoprim have been found. The compound 2-[(5-(adamantan-1-yl)-4-methyl-4H-1,2,4-triazole-3-yl)thio]-N’-(4-hydroxybenzyliden)acetohydrazide appeared to be more active than the reference drug in relation to E. coli and S. aureus.
Synthesis, the antifungal and antibacterial activity of N1-substituted N2-(4,5-dihydro-1,3-thiazol-2-yl)glycinamides
Aim. To apply cleavage of 2-methyl-2,3-dihydroimidazo[2,1-b][1,3]thiazol-(6H)-one with morpholine and piperidine for preparation of the previously unknown N1-substituted N2-(4,5-dihydro-1,3-thiazol-2-il)glycineamides as promising compounds for further study of the antibacterial properties.
Results and discussion. It has been shown that the reaction of 2-methyl-2,3-dihydroimidazo[2,1-b][1,3]thiazol-(6H)-one with the primary and secondary amines can be effectively used for the synthesis of N1-substituted N2-(4,5-dihydro-1,3-thiazol-2-il)glycineamides. Some glycinamides obtained demonstrate the antifungal and antibacterial properties in the range of concentrations of 7.81-62.50 mkg/ml.
Experimental part. 2-Methyl-2,3-dihydroimidazo[2,1-b][1,3]thiazol-(6H)-one reacts regioselectively with the primary and secondary amines in THF solution forming N1-substituted N2-(4,5-dihydro-1,3-thiazol-2-yl)glycineamides with the yields of 77-95%. Their structure has been proven by the complex spectral analysis. The screening of the antifungal and antibacterial properties of the compounds synthesized was conducted by the micromethod of double serial dilutions in the liquid nutritious medium.
Conclusions. It has been found that cleavage of 2-methyl-2,3-dihydroimidazo[2,1-b][1,3]thiazol-(6H)-one with the primary and secondary amines is a convenient method for the synthesis of N1-substituted N2-(4,5-dihydro-1,3-thiazol-2-il)glycineamides; among them substances with a marked antimicrobial activity have been found.