Synthesis and antitumor activity of new 1,2,4‐triazine and [1,2,4]triazolo[4,3‐b][1,2,4]triazine derivatives and their thioglycoside and acyclic C‐nucleoside analogs

New 1,2,4‐triazine and their derived 1,2,4‐triazolo[3,4‐b][1,2,4]triazine derivatives were synthesized starting from 5,6‐diphenyl‐1,2,4‐triazine‐3‐thiol. Furthermore, the corresponding 1,2,4‐triazolo[3,4‐b][1,2,4]‐triazine thioglycosides and acyclic C‐nucleoside analogs were synthesized. The newly synthesized compounds were evaluated for their antitumor activity and some of them showed high inhibition activities. J. Heterocyclic Chem., 2011.     

Synthesis and Anticancer Evaluation of Some Novel 5‐Amino[1,2,4]Triazole Derivatives

Novel [1,2,4]triazole derivatives were synthesized via various synthetic pathways. Among which were different substituted [1,2,4]triazole analogues that were synthesized, in addition to various fused [1,2,4]triazolo[1,5‐a]pyrimidine derivatives, [1,2,4]triazolo[1,5‐a][1,3,5]triazines, and [1,2,4]triazolo[5,1‐c][1,2,4]triazines. Besides, benzo[h][1,2,4]triazolo[5,1‐b]quinazolines, [1,2,4]triazolo‐[5,1‐b]quinazoline, [1,2,4]triazolo[1,5‐a]quinazoline and [1,2,4]triazolo[5,1‐d][1,2,3,5]tetrazine derivatives were also synthesized. The newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer HepG2 and breast cancer MCF7 cell lines compared with the reference drug doxorubicin. Compounds 4 , 7 , 15 , 17 , 28 , 34 , and 47 were found to exert promising anticancer activity against HepG2 cell line showing IC₅₀ values ranging from 17.69 to 25.4 μM/L, while compounds 7 , 14a , 17 , 28 , and 34 showed significant activity against MCF7 cell line with IC₅₀ values ranging from 17.69 to 27.09 μM/L.     

Synthesis and Antimicrobial Evaluations of Some Novel Mono‐, Bis‐, and Tris‐Nitro‐1,2,4‐Triazines

Substituted‐1,2,4‐triazines were conveniently synthesized in one pot by the cyclization of arylnitroformaldehyde hydrazone derivatives 1 and 5 with different primary amines in ~37% formaldehyde solution. The synthesized compounds were arranged into novel mono‐, bis‐, and tris‐nitro‐1,2,4‐triazine derivatives 2 , 3 , 4 , 6 , and 7 . The antibacterial and antifungal activity of the synthesized compounds were screened against bacterial strains Escherichia coli (as Gram − ve) and Staphylococcus aureus (as Gram + ve), and fungal strains Aspergillus flavus and Candida albicans . All the synthesized compounds exhibit various patterns of inhibitory activity on the two pathogenic bacterial strains. However, the same compounds showed no activity against the tested fungal strains.     

Synthesis and Antimicrobial Activity of New 2,5‐Disubstituted 1,3,4‐Oxadiazoles and 1,2,4‐Triazoles and Their Sugar Derivatives

A series of new 2,5‐disubstituted‐1,3,4‐oxadiazole and 1,2,4‐triazole derivatives were synthesized by heterocyclization of acid hydrazide 1 and thiosemicarbazide derivative 2 . Furthermore, the acyclic C‐nucleoside analogs were prepared by cyclization of their corresponding sugar hydrazones by reaction with acetic anhydride. The antimicrobial activity of the prepared compounds was evaluated and some of the synthesized compounds revealed good activities against fungi.     

Synthesis and Antimicrobial Evaluation of Novel Derivatives of Semicarbazide and 1,2,4‐triazole

Reaction of phenoxyacetic acid hydrazide with isocyanate was used to the synthesis of new semicarbazide derivatives. Cyclization of these compounds in a 2% aqueous solution of sodium hydroxide led to formation of 1,2,4‐triazole‐3‐one. The chemical structure of synthesized compounds was confirmed by elemental analysis and spectroscopic methods (¹H and ¹³C NMR). On the basis of the NMR, spectra were found that cyclic compounds 1,2,4‐triazole exist in the ‐one form. Moreover, all derivatives were examined for their in vitro activity against some species of bacteria. New compounds presented mild or moderate antimicrobial activity only against reference Gram‐positive bacteria. Two derivatives (one semicarbazide and one triazole) showed bactericidal or bacteriostatic activity.     

Synthesis and Antitumor Activity of New Substituted Mercapto‐1,2,4‐Triazine Derivatives,Their Thioglycosides,and Acyclic Thioglycoside Analogs

New 1,2,4‐triazine and their derived thioglycoside derivatives were synthesized from 5,6‐diphenyl‐1,2,4‐triazine‐3‐thiol. Furthermore, the corresponding acyclic thioglycoside analogs were synthesized from the corresponding mercapto derivatives and acyclic oxygenated alkyl halides. The newly synthesized compounds were evaluated for their antitumor activity and some of them showed high inhibition activities.     

Facile Synthesis of New [1,2,4]Triazolo[4,3‐b]pyridazine

A number of new [1,2,4]triazolo[4,3‐b]pyridazines were prepared by either cyclocondesation of substituted hydrazinopyridazines with orthoesters or oxidative cyclization of their hydrazone analogs in nitrobenzene as an oxidizing agent. A host of other new [1,2,4]triazolo[4,3‐b]pyridazine derivatives were synthesized by sequential treatment of the latter compounds with carbon disulfide and alkyl halides.     

A New Route to Synthesis of 3,6‐Diaryl‐1,2,4‐triazolo[3,4‐b]1,3,4‐oxadiazoles

Five new 3,6‐diaryl‐1,2,4‐triazolo[3,4‐b]1,3,4‐oxadiazole derivatives were synthesized by 9 steps from aromatic acids and evaluated for their activities of anticancer and antibacteria. The structures of all new compounds synthesized were elucidated by MS, IR, ¹HNMR and HRMS.     

Synthesis,structures, and biological activities of new 1H‐1,2,4‐triazole derivatives containing pyridine unit

Fourteen new 1H‐1,2,4‐triazole derivatives containing pyridine moiety were synthesized by condensation of 1‐(pyridine‐3‐yl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethanone with aryl aldehydes, and their reaction conditions were studied. The title compounds were screened for their antibacterial and plant growth regulatory activities. The screening data revealed that most of the compounds showed some antifungal and plant growth regulatory activities. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:376–380, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20308     

Synthesis,Characterization and Evaluation of Antimicrobial and Antituberculosis Activities of New N‐(Substituted‐thioureido)aminobicyclo Dicarboximide and 3,4‐Disubstituted 1,2,4‐Triazolino‐5‐thione

The novel N‐(substituted‐thioureido)aminobicyclo dicarboximide and 3,4‐disubstituted 1,2,4‐triazolino‐5‐thione were synthesized and their antimicrobial and antituberculosis activities were examined. Selected dicarboxylic acid anhydrides were used to obtain derivatives of thiosemicarbazide and dicarboximide. Dicarboximides were also cyclized in the presence of an alkaline solution giving 1,2,4‐triazolino‐5‐thione. The chemical structure of all compounds was confirmed by IR, ¹H NMR, ¹³C NMR, the X‐ray crystallography ( 6 , 11 ) and elemental analysis. Antimicrobial and antituberculosis activities of the derivatives were measured.     

Synthesis and Antimicrobial Activity of Some Condensed [4‐(2,4,6‐Trimethylphenyl)‐1(2H)‐oxo‐phthalazin‐2‐yl]acetic Acid Hydrazide

Some new 1,2,4‐triazolo‐, 1,3,4‐oxadiazolo‐, 1,3,4‐thiadiazol‐, and pyrazolo‐2,4,6‐trimethylphenyl‐1(2H)‐oxo‐phthalazine derivatives were synthesized and identified by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The new compounds were synthesized with the objective of studying their antimicrobial activity.     

Microwave‐Assisted Rapid and Efficient Synthesis of New Series of Chromene‐Based 1,2,4‐Oxadiazole Derivatives and Evaluation of Antibacterial Activity with Molecular Docking Investigation

A new series of novel chromene‐based oxadiazole derivatives were synthesized from a variety of chromene‐based amidoximes with readily available carboxylic acids under conventional oil bath heating as well as under microwave irradiation. The use of commercially available EDCI and HOBt as coupling reagents in DMF combined with microwave heating resulted in high yields and purities of the product 1,2,4‐oxadiazoles in an expeditious manner. This methodology is successfully applied to synthesize 18 numbers of new 2H‐chromene‐substituted 1,2,4‐oxadiazole derivatives in good to high yields. The structure of the product was ascertained by X‐ray crystallographic analysis. All the synthesized compounds were evaluated for their in vitro antibacterial activity against two different pathogenic bacterial strains, that is, Escherichia coli (MTCC614) and Klebsiella pneumoniae (MTCC4031). The obtained results from in vitro antimicrobial assays indicated that 6g and 6h exhibited good antibacterial activity nearer to the standard drug, gentamicin. The molecular docking studies showed that compounds 6g and 6h show hydrogen bonding interaction with the bacterial target DNA gyrase of E. coli.     

Synthesis and antimicrobial activity of some novel substituted 1,2,4‐triazoles bearing 1,3,4‐oxadiazoles or pyrazoles

Several derivatives of substituted 1,2,4‐triazole bearing the pyrazole (or oxadiazole) ring were synthesized via the reaction of 2,4‐dihydro‐4‐benzyl‐5‐(isomeric pyridyl)‐3H‐1,2,4‐triazole‐3‐thione 1a , 1b , 1c with ethyl chloroacetate, hydrazine hydrate, and acetyl acetone (or CS₂/KOH) in absolute ethanol. The intermediate then undergoes an intramolecular cyclization in acidic medium. The newly synthesized compounds 4a , 4b , 4c to 7a , 7b , 7c were characterized using IR, NMR, and MS Spectroscopy. Some of the synthesized compounds 4 , 5 , 7a , 7b , 7c were evaluated for their antibacterial and antifungal activities. Most of these compounds indicated activity comparable to Gentamycine. Also some of them are more active than Tolnaftate, a known antifungal drug. J. Heterocyclic Chem., (2011)     

Synthesis and Anticancer Activity Study of Some Novel Substituted and Fused Pyridotriazepine Derivatives

Various new substituted and fused pyridotriazepine analogues have been synthesized via different synthetic pathways. Among which are different heterocyclic compounds consisting of the pyridotriazepine backbone fused to different heterocyclic systems comprising either substituted pyrimidine nucleus such as compounds 3 – 9 or substituted 4‐aminopyridine nucleus such as compounds 10 – 16 . Besides, the tetrahydroquinoline derivative 17 , [1,2,4]triazolopyrimidine derivative 18 , thienodiazocine derivative 19 , dihydrobenzofuropyridine derivative 20 , and the substituted pyrrole derivative 21 were synthesized. In addition, different substituted pyridotriazepine derivatives as indicated in compounds 22 – 25 were designed and synthesized. Twenty‐five of the newly synthesized compounds were subjected to in vitro anticancer screening against mammalian colon carcinoma HCT‐116 cell line using Cisplatin as a reference drug. The anticancer activity screening results revealed that among the tested compounds, the tetrahydropyrido[1,2‐b]pyrimido[4,5‐e][1,2,4]triazepine derivative 4 substituted at C₂ and C₄ positions with S‐methyl and amino moieties, respectively, and the 2,4‐dithioxo analogue 9 and the 2‐thioxodipyrido[1,2‐b:2′,3′‐e][1,2,4]triazepine derivative 11 substituted at C₃ and C₄ with a cyano and amino moieties, respectively, exhibited moderate to strong anticancer activity against mammalian colon carcinoma HCT‐116 cell line.     

Synthesis and Antimicrobial Activity of New 1,2,3‐Triazolopyrimidine Derivatives and Their Glycoside and Acyclic Nucleoside Analogs

New [1,2,4‐oxadiazolyl]methyl‐3H‐[1,2,3]triazolo[4,5‐d]pyrimidin derivatives were synthesized starting from N′‐Hydroxy‐1‐naphthimidamide. The N‐substituted acyclic nucleoside analogs as well as the substituted glycosides were also prepared by reaction with the corresponding reagents. The antimicrobial results indicated that most of the tested compounds exhibited moderate to high antimicrobial activity whereas few compounds were found to exhibit little or no activity against the tested microorganisms.     

Synthesis and Biological Activity of Novel Ethyl Esters of 4‐R‐6,8‐Dimethyl‐1‐oxo‐1,2‐dyhidropyrrolo[1,2‐d][1,2,4]triazine‐7‐carboxylic Acids

The novel heterocyclizations of ethyl 5‐(hydrazinocarbonyl)‐2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylate are developed. New derivatives of ethyl esters of 4‐R‐6,8‐dimethyl‐1‐oxo‐1,2‐dyhidropyrrolo[1,2‐d][1,2,4]triazine‐7‐carboxylic acids were obtained. The in vitro anticancer and antibacterial activities of the synthesized compounds were revealed. The most potent antibacterial compound appeared to be 1.3 inhibiting Staphylococcus aureus. Pyrrolo[1,2‐d][1,2,4]triazine 2.15 showed significant antifungal activity against Candida tenuis. The anticancer activity of the synthesized compounds was determined.     

A Facile Synthesis of Aryl‐Substituted Hydrazono‐Pyrazolyl[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin Derivatives

Some inimitable and therapeutic coumarin‐substituted fused[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadizole derivatives were synthesized by the cyclocondensation reaction of 2‐oxo‐2H‐chromene‐3‐carboxylic acid ( 1 ) and 4‐amino‐5‐hydrazinyl‐4H‐[1,2,4]‐triazole‐3‐thiol ( 2 ) by using phosphorous oxychloride as a cyclizing agent. This cyclized intermediate 3‐(3‐hydrazino‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐chromen‐2‐one ( 3 ) later condensation with various ethyl 2‐(2‐arylhydrazono)‐3‐oxobutanoates ( 4 ) in NaOAc/MeOH under reflux conditions afforded the corresponding new series of aryl‐substituted hydrazono‐pyrazolyl‐[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin derivatives ( 5 ) in good to excellent yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR and mass spectroscopic studies.     

Synthesis,Modification, and Anticonvulsant Activity of 3′‐R1‐Spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones Derivatives

Previously unknown 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazoline]‐2,2′‐(7′H)‐diones and their N‐substituted analogues were obtained via reaction of 6‐R¹‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5‐ones with isatin and its substituted derivatives. It was shown that alkylation of 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′‐(7′H)‐diones by N‐R³‐chloroacetamides or chloroacetonitrile in the presence of а base proceeds by N‐1 atom of isatin fragment. The spectral properties (¹H and ¹³C NMR spectra) of synthesized compounds were studied, and features of spectral patterns were discussed. The high‐effective anticonvulsant and radical scavenging agents among 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones and their N‐substituted derivatives were detected. It was shown that compounds 2.2 , 2.8 , and 3.1 exceed or compete the activity of the most widely used in modern neurology drug—lamotrigine on the pentylenetetrazole‐induced seizures model. The aforementioned fact may be considered as a reason for further profound study of synthesized compounds using other pathology models.     

Synthesis of New 1,3,4‐Oxadiazol,Thiadiazole, 1,2,4‐Triazole,and Arylidene Hydrazide Derivatives of 4‐Oxo‐1,4‐dihydroquinoline with Antimicrobial Evaluation

A series of substituted 1,3,4‐oxadiazole, 1,2,4‐triazole, and 1,3,4‐thiadiazole derivatives of the substituted 3‐carboethoxy‐1,4‐dihydro‐4‐oxoquinoline have been synthesized through the reaction of the key intermediate thiosemicarbazide derivatives with different reagents. N′‐Arylidene‐4‐oxo‐1,4‐dihydroquinoline‐3‐carbohydrazides were also synthesized through the condensation reaction of the corresponding hydrazides with the appropriate aldehydes. Antimicrobial activity of some of the synthesized compounds was evaluated.     

Synthesis and evaluation of novel ferrocene‐substituted triadimenol analogues

In search of potent 1H‐1,2,4‐triazole derivatives with improving antifungal activity, a class of novel ferrocene–triadimenol analogues was synthesized and their biological potential evaluated. Screening data revealed that these new derivatives did not have the antifungal activities of parent compounds, but showed unexpectedly promising plant growth regulatory activity. Copyright © 2006 John Wiley & Sons, Ltd.