Hydrazino Derivatives Research Articles

Design, Synthesis and Anticancer Evaluation of New 1-allyl-4-oxo-6-(3,4,5- trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile Bearing Pyrazole Moieties.

pyrimidine and pyrazole have various biological and pharmaceutical applications such as antibacterial, antifungal, antileishmanial, anti-inflammatory, antitumor, and anti-cancer. In this search, the goal is to prepare pyrimidine-pyrazoles and study their anticancer activity. 1-allyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile bearing pyrazoles (4,6-8) have been synthesized. Firstly, the reaction of 1-allyl-2-(methylthio)-4-oxo-6- (3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile (1) with chalcones 2a-b produced the intermediates 3a-b. The latter was reacted with hydrazine hydrate to give the targets 4a-b. On the other hand, hydrazinolysis of compound 1 yielded the hydrazino derivative 5 which upon reaction with chalcones 2c-i or 1,3-bicarbonyl compounds afforded the compounds 6-8. Finally, the new compounds were characterized by spectral data (IR, 1H NMR, 13C NMR) and elemental analysis. Moreover, they were evaluated for Panc-1, MCF-7, HT-29, A-549, and HPDE cell lines as anticancer activity. All the tested compounds 3,4,6-8 showed IC50 values > 50 μg/mL against the HPDE cell line. Compounds 6a and 6e exhibited potent anticancer activity where the IC50 values in the range of 1.7- 1.9, 1.4-182, 1.75-1.8, and 1.5-1.9 μg/mL against Panc-1, MCF-7, HT-29, and A-549 cell lines. New pyrimidine-pyrazole derivatives were simply synthesized, in addition, some of them showed potential anticancer activity.

Synthesis and Spectroscopic Study of Some New 1,2,4-Triazino[5,6-b]indole Derivatives

The Scheme of this work included the synthesis and characterization of new two series of 1,2,4-triazino[5,6-b] indole and 8-bromo-1,2,4-triazino[5,6-b] indole derivatives according to the starting material used. Both, derivatives of 3-thione-1,2,4-triazino[5,6-b] indole and 8-bromo-3-thione-1,2,4-triazino[5,6-b] indole (3a & 3b) were prepared by using Isatin and 5-bromo isatin as a starting material, the new schiff`s bases (5a & 5b) were synthesized by the reaction of hydrazino indole derivatives (4a & 4b) with aromatic aldehydes. Tetracyclic derivatives (7a & 7b) were prepared by the reaction of hydrazino derivatives (4a & 4b) with carbon disulfide in the presence of pyridine. Also 3-(N-phenyl thiocarbamoyl hydrazino)-1,2,4-triazino-[5,6-b] indole, and 8-bromo-3-(N phenyl thiocarbamoyl hydrazino)-1,2,4-triazino-[5,6-b] indole (6a & 6b) were prepared by the reaction of the compound (4a & 4b) with phenyl thio isocyanate in the presence of DMF. Finally, new Mannich bases (9a & 9b) were prepared by the reaction of the new acetylenic indole derivatives (8a & 8b) with paraformaldehyde and secondary amine in the presence of coprous chloride as catalyst.
 These compounds were identified by their melting points and spectral data (IR & UV), and elemental analysis (C,H,N) and thin layer chromatography (TLC) were used.

Synthesis, characterization and antibiotic evaluation of various biologically active derivatives of 4-Alkylpyrimidine-5-carbonitrile

Extensive research work has been published on Tetrahydro and Dihydropyrimidine derivatives. Pyrimidine-5-Carbonitrile and its analogs have demonstrated a large number of activities. Some 6-Halogenosubstituted pyrimidine analogs have also been reported to be biologically active to a certain extent, but the literature survey reveals not much report on 6-alkylated pyrimidine derivatives. Targeting enhancement in biologically useful properties of a lead molecule through the association of it with active pharmacophoric groups or molecules is a conventional method in pharmaceutical research. With an aim to explore a better useful Dihydropyrimidine derivative, a newer 4-Alkylated-1,6-dihydropyrimidine analog (1) has been prepared. The lead molecule (1) has further been converted to amine derivative (2), hydrazino derivative (3) tri substituted s-triazinyl derivative (4), sulphonamide (5), Schiff’s base (6), a thiazolidinones (7), and 2-Azetidinones (8) respectively using various methods. Compounds 2, 4, 5, and 7 showed 50% and 8 showed 100% bacterial inhibition at 32μg/mL in single-point bacterial inhibition against various bacterial strains.

Mechanism of thermolysis of hydrazino-dinitroethylenes

Promising energetic materials – 1,1-diamino-2,2-dinitroethylene (DADNE) derivatives, in which one or two hydrogen atoms are replaced by –NH2 group, were studied by quantum-chemical calculations using hybrid functional PBE0 with cc-pVDZ basis set and coupled cluster method CCSD with aug-cc-pVDZ basis set. A number of thermolysis primary steps were investigated and it was shown that the addition of –NH2 group leads to a change in the mechanism of rate-limiting step. The main channels for DADNE are transfer of hydrogen to carbon and various transformations of aci-forms; for hydrazino derivatives hydrogen transfer to carbon is the only main channel and the following transformations are NO2 radical separation and transfer of another one hydrogen atom to an oxygen and elimination of HNO2 molecule.

Efficient access to some new pyrimidine derivatives and their antimicrobial evaluation

Abstract1‐[4‐(3‐Hydroxyphenyl)‐6‐methyl‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl]ethanone (1) was used as a precursor for heterocyclic synthesis. Condensation of compound 1 with monochloroacetic acid and benzaldehyde gave thiazolopyrimidine 2 which in turn underwent cyclization with malononitrile dimmer to afford malononitrile derivative 3. Also, the reaction of compound 1 with benzaldehyde under a basic condition produced chalcone 4. Chalcone 4 can be used as a key intermediate for further preparation of heterocyclic compounds. In addition, compound 1 was allowed to react with malononitrile dimmer and/or ethyl chloroacetate to give pyrimidines 8 and 9, respectively. Alkylation of compound 8 with ethyl chloroacetate afforded S‐alkylated product 10 which was treated with hydrazine hydrate to yield the hydrazino derivative 11. Alternative synthesis of compound 10 was taken place through reaction of compound 9 with malononitrile dimmer. The biological activity of the synthesized compounds was investigated. Compounds 1, 4, 5, and 8 recorded high activities against Gram positive bacteria (S. aureus). Structures of the new synthesized compounds were elucidated by elemental analysis and spectral data.

Dimroth rearrangement-based synthesis of novel derivatives of [1,3]selenazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine as a new class of selenium-containing heterocyclic architecture.

As a part of our ongoing endeavor towards developing novel heterocyclic architectures, a number of novel Se-containing tricyclic heterocycles of the type [1,3]selenazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine have been synthesized through heteroannulation of a newly produced hydrazino derivative of selenazolo[4,5-d]pyrimidine with either orthoesters or carbon disulfide in pyridine followed by S-alkylation. Moreover, the multistep protocol employed in this investigation provides a new insight into the Dimroth rearrangement in both acidic and basic media as a means for the cyclocondensation of triazole on the selenazolopyrimidine framework leading to selenazolotriazolopyrimidines. The synthesis of new derivatives of novel selenazolotriazolopyrimidines via Dimroth rearrangement in both acidic and basic media is presented.

Straightforward synthesis, antiproliferative screening, and density functional theory study of some pyrazolylpyrimidine derivatives

AbstractTetrahydropyrimidinone derivative was synthesized through one‐pot three components condensation of 1,3‐diphenylpyrazole‐4‐carbaldehyde with pentan‐2,4‐dione and urea under Biginelli reaction conditions. The corresponding chloro‐ and hydrazino derivatives were synthesized and utilized for the construction of some valuable N‐heterocycles encompassing both pyrazole and pyrimidine cores, such as triazolopyrimidine, tetrazolopyrimidine, pyrazole, and pyrazolone derivatives through condensation with nitrogen nucleophiles and carbon electrophiles. The antiproliferative activity evaluation of the synthesized compounds against four human carcinoma cell lines namely, liver carcinoma (HepG2), breast adenocarcinoma (MCF7), prostate cancer (PC3), and colon cancer (HCT‐116) cell lines revealed that some of them provided significant potency, as well as the density‐functional theory (DFT) was studied. The permeability of various hydrophilic and hydrophobic synthesized compounds across both normal and cancer cells is confirmed via DFT simulation in which the much higher permeability through aquaporin channels revealed the selective cytotoxicity toward cancer cells.

Synthesis of 3‐cyano‐2‐pyridone derivative and its utility in the synthesis of some heterocyclic compounds with expecting antimicrobial activity

AbstractNew 2‐pyridone derivatives bearing p‐methoxyphenyl and p‐bromophenyl substituents at C‐4 and C‐6 were prepared smoothly by the one‐pot reaction in high yield, and in a comparatively short time, it reacted with phosphorous oxychloride to produce the corresponding chloro compound. The latter was reacted with several nitrogen nucleophiles such as sodium azide, hydrazine, acetohydrazide, and benzohydrazide to give tetrazolo, hydrazino, and triazolo derivatives, respectively. The reaction of hydrazino derivative with cyclopentanone, furan‐2‐carbaldehyde afforded the corresponding hydrazone derivatives. Cyclocondensation of the latter compounds with thioglycolic acid afforded the nicotinamide derivatives. 2‐Pyridone reacted with ethyl chloroacetate to afford chloroacetate and ethyl acetate derivatives. Ethyl acetate‐derivative reacted with hydrazine hydrate and gave the acetohydrazide derivative, it was condensed with p‐anisaldehyde and gave the 4‐methoxybenzylidene acetohydrazide derivative. Also, 2‐pyridone reacted with chloroacetic acid and or benzoyl chloride, afforded the benzoate derivative and 2‐((6‐(4‐bromophenyl)‐3‐cyano‐4‐(4‐methoxyphenyl) pyridin‐2‐yl) oxy) acetic acid, respectively. Structures of the products were confirmed using spectroscopic data and elemental analyses. Antibacterial activity of the synthesized compounds was evaluated against Escherichia coli and Staphylococcus aureus.

Synthesis, reactions, and antimicrobial activity of some novel pyrazolo[3,4‐d]pyrimidine, pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidine, and pyrazolo[4,3‐e][1,2,4]triazolo[3,4‐c]pyrimidine derivatives

AbstractTreatment of N‐phenyl‐substituted benzenecarbo‐hydrazonoyl chlorides 1a‐d with malononitrile in sodium ethoxide solution gave 5‐amino‐4‐cyanopyrazole derivatives 2‐5. Compounds 2‐5 were converted to formidate derivatives 6‐9 upon treatment with TEOF in acetic anhydride. The reaction of the latter products 6‐9 with hydrazine hydrate gave imino‐amino derivatives 10‐13, which was converted to hydrazino derivatives 14‐17 by refluxing with hydrazine hydrate. Hydrazino as well as imino‐amino derivatives undergo condensation, cyclization, and cycloaddition reactions to give pyrazolo[3,4‐d]pyrimidine 18‐21, pyrazolo[4,3‐e][1,2,4]triazolo‐[3,4‐c]pyrimidine 22‐27, and pyrazolo[3′,4′:4,5]pyrimido[1,6‐b][1,2,4]triazine 42‐44 derivatives. Antimicrobial studies are performed using two Gram‐positive bacteria and two Gram‐negative bacteria. Data indicated that compounds 5, 28D, 29B, and 31D are exploring elevated antibacterial effects against all strains tested. Compound 28D is the most promising antibacterial agent against the delicate bacterial strain Bacillus subtilis and Pseudomonas aeruginosa with high effectiveness (low minimum inhibitory concentration [MIC] value) 40 and 60 μg/mL, respectively.

Synthesis, Cytotoxicity, Antimicrobial and Docking Simulation of Novel Pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c] pyrimidine Derivatives.

Isobutyrohydrazonoyl bromide 1 was used as a precursor for the synthesis of 4-imino-3-isopropyl-1-(4-nitrophenyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine 4, which was converted into hydrazino derivative 5 by heating with hydrazine hydrate at reflux. Hydrazino, as well as imino-amino derivatives, underwent condensation and cyclization reactions to give pyrazolo[ 3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c]pyrimidine derivatives, respectively. Antimicrobial studies are performed using two-gram positive bacteria and two-gram negative bacteria. Data revealed that compound 9a is the most promising antibacterial agent with high efficiency (low MIC value (48 μg/ml)). The cytotoxic assay was investigated for in vitro antitumor screening against Caucasian breast adenocarcinoma MCF7, hepatocellular carcinoma HepG2 and colon carcinoma HCT-116 cell lines. The results are compared with doxorubicin standard anticancer drugs as well as normal cell lines like MCF10 and MCF12. Molecular docking was carried out for the highest potent compound 8c with the binding site of dihydrofolate reductase enzyme DHFR PDB:ID (1DLS).

Understanding the tetrazole ring cleavage reaction with hydrazines: Structural determination and mechanistic insight

A distinction in the behaviour of several hydrazines as N-nucleophiles in the recently developed one-pot method for pyrimidine core annulation via 1H-tetrazole ring cleavage was examined. The product structures, 2,3-diamino- or hydrazino derivatives of thieno[3,2-d]pyrimidin-4(3H)-ones, thieno[2,3-d]pyrimidin-4(3H)-ones and [1]benzofuro[3,2-d]pyrimidin-4(3H)-one, were elucidated based on NMR and single crystal X-ray analysis.

Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents

ABSTRACTA new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil 1 was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine 2. On the other hand, treatment of cyanouracil 1 with 2-chloro-N-substituted-phenylac etamide afforded 4. Hydrazinolysis of 6 afforded the hydrazino derivatives 7 which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives 8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds 7 and 9 have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested in vitro for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds 7, 9, and 2d displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme.

Hydrazino-methoxy-1,3,5-triazine Derivatives' Excellent Corrosion Organic Inhibitors of Steel in Acidic Chloride Solution.

The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT), 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT), and 2,4,6-tridydrazino-1,3,5-triaizne (TH3) on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT) gave the best corrosion protection performance among the other hydrazino derivatives even at a low concentration of 25 ppm (95%). The number of hydrazino groups play an important role in the corrosion inhibition, where the two hydrazine groups increased the electrostatic interactions between the protonated tested compounds, the negatively charged steel surface resulted from the adsorption of the chloride anions, and the presence of the methoxy group made the compound more reliable for formation of film protection on the surface of steel through the lone pair of oxygen atoms. Electrochemical Impedance Spectroscopy (EIS) measurements suggested that the corrosion process of steel in presence of the hydrazino-s-triazine derivatives (TH3, DMeHT and DHMeT) were being controlled by the charge transfer reaction. Polarization curves indicated that the examined TH3, DMeHT and DHMeT behaved as mixed type inhibitors.

Synthesis of Novel Derivatives of Imidazo[2,1-c][1,2,4]Triazine from Biologically Active 4-Arylidene-2-Hydrazino-1-Phenyl-1H-Imidazol-5(4H)-Ones and Evaluation of their Antimicrobial Activity

4-Arylidene-2-hydrazino-1-phenyl-1H-imidazolin-5(4H)-ones were synthesised and used as key intermediates for the synthesis of novel imidazo[2,1-c][1,2,4]triazine derivatives. The new imidazo[2,1-c][1,2,4]triazine derivatives were obtained via the reaction of the hydrazino derivatives with pyruvic acid, chloroacetyl chloride and phenacyl bromide derivatives respectively. Structures of the newly synthesised compounds were confirmed using spectral data as well as elemental analysis. Seven compounds were evaluated for their antimicrobial activity with minimum inhibitory concentration (MIC) values against several reference strains of bacteria and fungi, with ampicillin, gentamicin and amphotericin B used as comparison drugs. It was observed that most of the evaluated compounds showed high antibacterial as well as antifungal activities. 6-(4-Chlorobenzylidene)-4-(4-methylphenyl)-8-phenyl-6,8-dihydroimidazo-[2,1-c][1,2,4] triazin-7(2H)-one was the most potent compound with high inhibition zones and low MIC values.

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids.

Peptidomimetics based on hydrazino derivatives of α-amino acids represent an important class of peptidic foldamers with promising biological activities, like protease inhibition and antimicrobial activity. However, the lack of straightforward method for the synthesis of optically pure hydrazino acids and efficient incorporation of hydrazino building blocks into peptide sequence hamper wider exploitation of hydrazino peptidomimetics. Here we described the utility of Nα-benzyl protected and unprotected hydrazino derivatives of natural α-amino acids in synthesis of peptidomimetics. While incorporation of Nα-benzyl-hydrazino acids into peptide chain and deprotection of benzyl moiety proceeded with difficulties, unprotected hydrazino acids allowed fast and simple construction of hybrid peptidomimetics.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1288-9) contains supplementary material, which is available to authorized users.

Synthesis of New Derivatives of Pyrazolo[4,3-e][1,2,4]Triazolo[4,3-c]Pyrimidine

A number of new derivatives of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine have been synthesised by cyclocondensation of several hydrazino derivatives of pyrazolo[3,4-d]pyrimidine with either orthoesters or carbon disulfide in pyridine followed by alkylation to obtain the desired products. The structures of all the newly synthesised products have been thoroughly elucidated.

Synthesis of (piperidin-1-yl)trihydropyrano(cyclopenta)-[4′,5′]pyrido[3′,2′: 4,5]thieno[3,2-e][1,2,4]triazolo-[4,3-c(1,5-c)]pyrimidines

Reactions of 3-cyanopyridine-2(1H)-thiones with ethyl chloroacetate and chloroacetamide gave the corresponding amino-substituted thieno[2,3-b]pyridines which were treated with formamide or ethyl formate to obtain fused pyridothieno[3,2-d]pyrimidinones. The latter were converted into hydrazino derivatives whose cyclocondensation with triethyl orthoformate or formic acid afforded 7,10-dihydro-8H-pyranopyridothienopyrimidines and 2,3-dihydro-1H-cyclopentapyridothienopyrimidines annulated by triazole ring at the pyrimidine ring.

ChemInform Abstract: Synthesis and Structure of Condensed Triazolo‐ and Tetrazolopyrimidines.

AbstractHydrazino derivatives (I) and (VI) undergo ring closure reactions by treatment with triethyl orthoformate (II), formic acid (IV) and nitrous acid to give the title compounds in good yields.

Synthesis and structure of condensed triazolo- and tetrazolopyrimidines

Herein we present the synthesis of several new hydrazino derivatives of cyclopenta[c]pyridine, 5,6,7,8-tetrahydroisoquinoline and pyrano[3,4-c]pyridine from 3-oxo-4-cyano fused pyridine derivatives. The hydrazino derivatives obtained were used as starting materials for the synthesis of isomeric triazolopyrimidines as well as tetrazolopyrimidines. Furthermore, the rearrangement of triazolopyrimidines 7 into triazolopyrimidines 8 is also presented. In DMSO tetrazolopyrimidines 10 were shown to be in equilibrium with the relevant azidopyrimidines 9. The tetrazolopyrimidine structure was confirmed by X-ray crystallography. The synthesized compounds were tested for their antimicrobial activity.

Heteroannulation of Pyrido[2,3-d]Pyrimidines. Synthesis and Spectral Characterization of Pyridotriazolopyrimidines, Pyridopyrimidotriazine and Pyridopyrimidotriazepine Derivatives

Number of pyridotriazolo-, pyridothiazolo-, pyridotetrazolopyrimidines and pyrido-pyrimidotriazepine derivatives were prepared using the readily obtainable starting material pyrido[2,3-d]pyrimidinthione<SUP>1</SUP> and its hydrazino derivative. The antimicrobial screening of selected synthesized compounds was done using the agar diffusion assay. The IR, <SUP>1</SUP>H NMR and mass spectra of the synthesized compounds were investigated.