Khim. Geterotsikl. Soedin.

Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a–g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one fungus i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. In vitro antiplasmodial IC50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

/pdf/design-synthesis-conformational-and-molecular-docking-study-bbdfwe89vj.pdf

Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents

The review focuses on the methods of synthesis of 2-(1-alkoxyalkylidene)-1,3-dicarbonyl compounds and their chemical transformations. The reactivity of such compounds toward various mono- and dinucleophilic reagents is considered. The potential of these compounds for synthesis of different acyclic, carbo- and heterocyclic molecules is demonstrated. Special attention is paid to the practical use of 2-(1-alkoxyalkylidene)-1,3-dicarbonyl compounds and their derivatives, which are of interest in medicine and for design of new materials. The bibliography includes 226 references.

The use of 2-(1-alkoxyalkylidene)-1,3-dicarbonyl compounds in organic synthesis

This review provides comprehensive data (from the author's work and the literature) on tautomerism of pyrazoles, imidazoles, 1,2,3- and 1,2,4-triazoles, tetrazoles, benzimidazoles, benzimidazolones, benzotriazoles, and related compounds by multinuclear 1 H, 13 C, 15 N nuclear magnetic resonance (NMR) spectroscopy. Emphasis is given to studies of azoles by multinuclear dynamic NMR spectroscopy because prototropic transformations of almost all azoles in solution proceed so quickly. Quantum-chemical investigations of tautomeric azoles are covered in detail. Critical analysis of literature data on the tautomerism of azoles is presented. Theoretical studies of structure and reactivity of azoles are most intriguing because correct interpretation of their chemical behavior and biological activity depends on an understanding the factors determining relative stability of their tautomers. 15 N NMR spectroscopy is the most reliable and fast technique for structural and tautomeric determination of nitrogen-containing heteroaromatic compounds.

Tautomerism and Structure of Azoles: Nuclear Magnetic Resonance Spectroscopy

A compound exhibits (prototropic) tautomerism if it can be represented by two or more structures that are related by a formal intramolecular movement of a hydrogen atom from one heavy atom position to another. When the movement of the proton is accompanied by the opening or closing of a ring it is called ring–chain tautomerism. This type of tautomerism is well observed in carbohydrates, but it also occurs in other molecules such as warfarin. In this work, we present an approach that allows for the generation of all ring–chain tautomers of a given chemical structure. Based on Baldwin’s Rules estimating the likelihood of ring closure reactions to occur, we have defined a set of transform rules covering the majority of ring–chain tautomerism cases. The rules automatically detect substructures in a given compound that can undergo a ring–chain tautomeric transformation. Each transformation is encoded in SMIRKS line notation. All work was implemented in the chemoinformatics toolkit CACTVS. We report on the appl...

Enumeration of ring-chain tautomers based on SMIRKS rules.

Mercaptoacetylhydrazones of aliphatic and aromatic aldehydes exist in the solutions as tautomeric mixtures of open-chain and cyclic 1,3,4-thiadiazine forms. The linear hydrazone form consists of a set of isomers due to the configurational and conformational isomerism. At growing bulk of the alkyl substituent at the C=N bond of the aliphatic aldehydes derivatives decreases the fraction of the cyclic tautomer; therewith the logarithms of the constants of the chain-ring tautomeric equilibrium correlate with the steric constants of the alkyl substituents. In the series of the aromatic aldehydes mercaptoacetylhydrazones the linear tautomer prevails, and the equilibrium position is insignificantlyt affected at variation of the electronic characteristics of the substituents in the aromatic ring.

Tautomerism and conformational isomerism of mercaptoacetylhydrazones of aliphatic and aromatic aldehydes

Acylhydrazines react with 1,3-diketones of the general formula CF3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.

Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products

Reactions of 3-ethoxymethylidenepentane-2,4-dione and ethyl 2-ethoxymethylidene-3-oxobutanoate with benzohydrazide

Condensation products of aliphatic aldehydes with 3-sulfanylpropionic acid hydrazide exist in solution as mixtures of linear hydrazone and cyclic 1,3,4-thiadiazepine tautomers. Hydrazones derived from 3-sulfanylpropionic acid hydrazide and aromatic aldehydes and ketones have mostly linear structures of different stereoisomers arising from Z-E isomerism with respect to the double C=N bond and restricted rotation about the C(O)-N bond. Condensation products of 3-sulfanylpropionohydrazide with a series of aldoses give rise to ring-chain-ring tautomeric equilibrium between α,β-isomeric pyranose structures, open-chain aldose hydrazone tautomer, and two diastereoisomeric seven-membered cyclic 1,3,4-thiadiazepine forms.

Structure of the condensation products of 3-sulfanylpropionic acid hydrazide with aldehydes, ketones, and aldoses

Condensation products of thioglycolic acid hydrazide with aldoses (L-arabinose, D-xylose, L-rhamnose, D-galactose, D-glucose, D-mannose) exist in the D2O solution as a tautomeric mixture of α,β-pyranose form and six-membered 1,3,4-thiadiazine form present as two diastereomers.

I. V. Zerova

Papers

Tautomerism and conformational isomerism of mercaptoacetylhydrazones of aliphatic and aromatic aldehydes

Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products

Reactions of 3-ethoxymethylidenepentane-2,4-dione and ethyl 2-ethoxymethylidene-3-oxobutanoate with benzohydrazide

Structure of the condensation products of 3-sulfanylpropionic acid hydrazide with aldehydes, ketones, and aldoses

Structure of products of aldoses condensation with thioglycolic acid hydrazide