Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

Synthesis,Antiviral, and Antimicrobial Activity of N‐ and S‐Alkylated Phthalazine Derivatives

A series of N‐alkylphthalazinone were synthesized by the reaction of phthalazin‐1(2H)‐one derivatives 1a , 1b , 1c with alkylating agents namely, propargyl, allyl bromide, epichlorohydrin, 1,3‐dichloro‐2‐propanol, 4‐bromobutylacetate, and 1‐(bromomethoxy)ethyl acetate to give the corresponding N‐alkylphthalazinone 2a , 2b , 2c , 3a , 3b , 3c , 5a , 5b , 5c , 6a , 6b , 6c , 7a , 7b , 7c , and 9a , 9b , 9c . Alkylation of phthalazin‐1(2H)‐thione to give a series from S‐alkylphthalazine 12 , 13 , 14 and thioglycosides 15 and 17 was performed. Deprotection of compounds 7a , 7b , 7c , 9a , 9b , 9c , 15 , and 17 resulted in the formation of the corresponding products 8a , 8b , 8c , 10a , 10b , 10c , 16 , and 18 . The structure of newly synthesized compounds was assigned by IR, ¹H, ¹³C NMR, and elemental analysis. Some of these compounds were screened for antiviral and antimicrobial activity.     

Synthesis and antimicrobial activity of some heterocyclic 2,6‐bis(substituted)‐1,3,4‐thiadiazolo‐, oxadiazolo‐, and oxathiazolidino‐pyridine derivatives from 2,6‐pyridine dicarboxylic acid dihydrazide

In this work, we report on the synthesis and preliminary biological activity screening of several heterocyclic derivatives 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 10a , 10b , 11 , 11a , 11b , 12 , 12a , 12b , 13 , 13a , 13b , 14 , 15 based on N2′,N6′‐diphenylthiosemi‐carbazide pyridine‐2,6‐dicarbohydrazide 2 , which has been obtained from the corresponding dihydrazide 1 . The biological screening showed that many of these compounds have good antimicrobial activities. The structure of the new compounds has been established on the bases of chemical and spectroscopic evidences. J. Heterocyclic Chem., (2011).     

Novel synthetic protocol toward pyrazolo[3,4‐h]‐[1,6]naphthyridines via Friedlander condensation of new 4‐aminopyrazolo[3,4‐b]pyridine‐5‐carbaldehyde with reactive α‐methylene ketones

Novel pyrazolo[3,4‐h][1,6]naphthyridine derivatives 6 , 8 , 9 , 11 , 13 , and 15 have been synthesized by Friedlander condensation of new 4‐amino‐3‐methyl‐1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbaldehyde (o‐aminoaldehyde) 4 with active methylene ketones, such as symmetric acetone 5a , monoalkylketones 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , unsymmetrical dialkyl ketones 7a , 7b , p‐bromophenylacetonitrile 10 , β‐ketoester 12a , β‐ketoamide 12b , or diethyl malonate 14 , respectively. J. Heterocyclic Chem., (2011).     

Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2‐Pyrazolines

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2‐pyrazolines having a basic side chain at C‐3 and a phenolic Mannich base at C‐5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3‐functionalized 2‐pyrazolines) 7 and 9 . The transamination between the styryl keto base 10 and 4‐aminoantipyrine leads to 12 , which reacts with piperazine to give 13 . N‐Nitrosation of the sec‐Mannich bases 15a – d followed by reductive cyclization affords 2‐pyrazolines 17a – d . The keto base 14b has been used for the synthesis of 2‐pyrazolines having a phenolic Mannich base at C‐3 and its reaction with 3,5‐dimethyl‐1H‐pyrazole affords 23 . The alkylation of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one with the bis(Mannich base) 25 was investigated.     

Synthesis and Reactions of Some New Benzo[a]phenothiazine‐3,4‐dione Derivatives

The reaction of 2,3‐dihydro‐2,3‐epoxy‐1,4‐naphthoquinone ( 4 ) with substituted anilines furnished the corresponding benzo[fused]heterocyclic derivatives 5 , 6 , 6a , 6b , 7 , 8 . Furthermore, treatment of benzo[a]phenothiazine derivative 7 with halo compounds, namely, ethyl bromoacetate, phenacyl bromide, dibromoethane, or chloroacetone afforded ether derivatives 11 , 12 , 13 , 14 , respectively. Moreover, the reaction of 11 with o‐substituted aniline gave the corresponding benzo[a]phenothiazin‐5‐one derivatives 15 , 16 , 17 and benzo[d][1,3]oxazin‐4‐one 18 , respectively. Finally, the chromenone derivative 19 was synthesized via the reaction of ester derivative 11 with salicyaldhyde in refluxing pyridine. The newly synthesized compounds were characterized by spectroscopic measurements (IR, ¹H NMR, ¹³C NMR, and mass spectra).     

A new approach to the synthesis of benzofuro[3,2‐b]quinolines,benzothieno[3,2‐b]quinolines and indolo[3,2‐b]quinolines

Treatment of 2‐hydroxy‐, 2‐mercapto‐, and 2‐ethoxycarbonylamino‐benzonitriles 12 with 2‐fluoro‐ or 2‐nitrophenacylbromides 13 under alkaline conditions provided the corresponding benzofuran, benzothiophene, and indole intermediates 10 , respectivelly. Nucleophilic cyclization of these compounds led to the corresponding tetracyclic quinolinones 7a, 7b , and 3. Denitrocyclization reaction of compounds 10 (R = NO₂) was found especially useful. Compounds 7a, 7b , and 3 were converted to their chloro derivatives 14a‐c , which were reduced with hydrogen and a catalyst to the corresponding compounds 8a, 8b , and 2. The presented pathway represents a new method of preparation of quindoline 2 and its O and S analogs 8. Chloro derivatives 14 are reactive enough to provide the corresponding methoxy derivatives 15 and dimethylamino derivatives 16. Methylation of compounds 7a and 7b with iodomethane providing mixtures of major N‐methyl derivatives 17 and minor O‐methyl derivatives 15 were also studied.     

3,4‐Bis(bromomethyl)thieno[2,3‐b]thiophene: Versatile Precursors for Novel Bis(triazolothiadiazines), Bis(quinoxalines), Bis(dihydrooxadiazoles), and Bis(dihydrothiadiazoles)

A synthesis of novel bis(triazolothiadiazines) 11 , 12 , 13 , 14 , bis(quinoxalines) 16 and 17 , bis(thiadiazoles) 24 and 25 , and bis(oxadiazole) 31 , which are linked to the thieno[2,3‐b]thiophene core via phenoxymethyl group, was reported. Thus, reaction of the bis(α‐bromoketones) 6 and 7 with the corresponding 4‐amino‐3‐mercapto‐1,2,4‐triazole derivatives 8 , 9 , 10 in ethanol–DMF mixture in the presence of a few drops of triethylamine as a catalyst under reflux afforded the novel bis(5,6‐dihydro‐s‐triazolo[3,4‐b]thiadiazines) 11 , 12 , 13 , 14 in 60–72% yields. The bis(quinoxalines) 16 and 17 were also synthesized as a sole product in high yields by the reaction of 6 and 7 with o‐phenylenediamine 15 in refluxing acetonitrile in the presence of piperidine as a catalyst. Cyclization of the bis(aldehyde thiosemicarbazones) 20 and 21 with acetic anhydride afforded the corresponding bis(4,5‐dihydro‐1,3,4‐thiadiazolyl) derivatives 24 and 25 in good yield. Bis(5‐phenyl‐2,3‐dihydro‐1,3,4‐oxadiazole) derivative 31 could be obtained in 67% yield by cyclization of the appropriate bis(N‐phenylhydrazone) 29 in refluxing acetic anhydride for 3 h.     

Efficient Routes for the Synthesis of Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines)

Bis(triazolo[3,4‐b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be synthesized in 75% yield by, firstly, preparation of bis(s‐triazole) 2 followed by reaction with phenacyl bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of thiocarbohydrazide 6 to give the corresponding bis(4‐amino‐5‐mercapto‐s‐triazolo‐3‐y1) derivatives 7 and 10 and subsequent reaction with two equivalents of phenacyl bromide. Bis(6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines) 15a , 15b , 15c , 15d , 15e , 15f , which are linked to arene cores via sulfanylmethylene spacers, were prepared by the reaction of 4‐amino‐4H‐1,2,4‐triazole‐3,5‐dithiol 12 with the appropriate bis(bromomethyl)benzenes 13a , 13b , 13c , 13d , 13e , 13f to give bis(4‐amino‐5‐mercapto‐4H‐3‐sulfanylmethyl)arenes 14a , 14b , 14c , 14d , 14e , 14f and subsequent reaction with phenacyl bromide. Compounds 15a , 15b , 15c , 15d , 15e , 15f were alternatively obtained in 60–70% yields by twofold substitution of 13a , 13b , 13c , 13d , 13e , 13f with two equivalents of 6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine‐3‐thiol 16 in refluxing EtOH/DMF mixture containing KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage was prepared in 70% yield starting from p‐phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride 18 followed by bis‐alkylation with 1,2,4‐triazole 20 and subsequent intramolecular ring closure upon treatment with phosphorus oxychloride.     

Syntheses of [1,2,3]selenadiazolo[4,5‐e]benzofuran or benzothiophene, [1,2,3]thiadiazolo[4,5‐e]benzofuran or benzothiophene,and 2‐benzofuranyl‐1,3,4‐oxodiazole derivatives

Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively.     

Synthesis of some novel pyrazoline‐thiazole hybrids and their antimicrobial activities

A series of novel thiazolyl pyrazolines 7a‐h , 9a‐f , and 11a‐f have been synthesized by the reaction of thioamide derivatives 5a , b with 1‐aryl‐2‐bromoethanones 6a‐d , chloroacetones 8a‐c , and hydrazonoyl chlorides 10a‐c . Additionally, pyrazoles 15a‐c and 20 were prepared starting from enaminone 13 . These newly synthesized compounds were screened for their in vitro antibacterial activity against four bacterial species. Compound 11b showed a moderate activity against Klebsiella pneumoniae. Compounds 7c and 11c revealed a moderate activity against Pseudomonas aeruginosa. In addition, the antifungal activity of the newly synthesized compounds was determined against five fungal strains. Compounds 7e , 7g , and 11e showed a good activity against Aspergillus flavus and Penicillium expansum.     

Synthesis,Characterization, and Antioxidant Evaluation of Some Novel Pyrazolo[3,4‐c][1,2]diazepine and Pyrazolo[3,4‐c]pyrazole Derivatives

5‐Hydrazineyl‐3‐methyl‐1H‐pyrazole ( 1 ) was used as a starting material for the synthesis of novel pyrazolo[3,4‐c][1,2]diazepine derivatives 3 , 4 , and 6a,b by its reaction with acetylacetone, ethyl acetoacetate, and isatylidene derivatives 5a,b , respectively. Also, pyrazolo[3,4‐c][1,2]diazepine derivative 11 was synthesized via multicomponent reaction of 1 , benzaldehyde, and malononitrile. Moreover, compound 1 was used for synthesis novel pyrazolo[3,4‐c]pyrazole derivative 7 by its reaction with isatin. In addition, pyrazolo[3,4‐c]pyrazole derivatives 18a–c were synthesized by treatment of 2‐cyano‐N′‐(3‐methyl‐1H‐pyrazol‐5‐yl)acetohydrazide ( 13 ) with aromatic aldehydes 16a–c . The newly synthesized compounds were valeted by means of analytical and spectral data. All newly synthesized compounds were screened for their antioxidant activities. Compounds 3 , 13 , 18b , and 18c showed higher radical‐scavenging activities.     

5‐Chloro‐3‐methylthio‐1,2,4‐thiadiazol‐2‐ium chlorides as useful synthetic precursors to a variety of 6aλ4‐thiapentalene systems

Title salts 3 were easily obtained by treatment of formimidoyl isothiocyanates 1 with a twofold excess of methanesulfenyl chloride. They showed interesting chemical behavior toward several nitrogen and carbon nucleophiles. Substitution reactions with isothioureas and acetamide in the presence of triethylamine gave the 1H, 6H‐6aλ⁴‐thia‐1,3,4,6‐tetraazapentalenes 7 and 6H‐6aλ⁴‐thia‐1‐oxa‐3,4,6‐triazapentalene 9 , respectively. Addition of p‐toluidine furnished the 5‐imino‐thiadiazole derivatives 10 , which reacted further with diverse heterocumulenes to yield the corresponding thiatriaza‐ and tetraazapentalene species 11 . The N,N′‐bis(1,2,4‐thiadiazol‐5‐ylidene)diaminobenzenes 13 were also prepared and reacted with phenyl isothiocyanate. Two stable rotational isomers were separated for the 1,2‐phenylene product 14b . Other π‐hypervalent sulfur compounds 16 were synthesized under similar conditions from salts 3 and methyl cyanoacetate or dimethyl malonate. The structural assignments were discussed on the basis of IR and NMR spectroscopic data and received additional support from X‐ray analysis of substrate 16a . © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:95–105, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10106     

Synthesis and biological evaluation of several 3‐(coumarin‐4‐yl)tetrahydroisoxazole and 3‐(coumarin‐4‐yl)dihydropyrazole derivatives

A series of novel 3‐(coumarin‐4‐yl)tetrahydroisoxazoles 5a,b, 7, 9 and 3‐(coumarin‐4‐yl)dihydropyra‐zoles 13a‐d, 14,15a,b were synthesized from coumarin‐4‐carboxaldehyde 1 via the intermediate N‐methyl nitrone 3 and N‐phenyl or N‐methyl hydrazones 11a,b . These coumarin derivatives were isolated, characterized and evaluated in vitro for their ability to inhibit trypsin, β‐glucuronidase, soybean lipoxygenase and to interact with the stable radical 1,1‐diphenyl‐2‐picrylhydrazyl. The compounds were tested in vivo as anti‐inflammatory agents in the rat carrageenin paw edema assay. Compound 15a seems to be a lead molecule to be modified in order to improve the lipoxygenase inhibition. The results are discussed in terms of structural characteristics.     

Microwave‐Assisted Synthesis of Arylated Pyrrolo[2,1‐a]Isoquinoline Derivatives via Sequential [3 + 2] Cycloadditions and Suzuki‐Miyaura Cross‐Couplings in Aqueous Medium

Treatment of 5‐bromo‐2‐(bromoacetyl)thiophene ( 1 ) with isoquinoline gave the isoquinolinium bromide 2 . Reaction of 2 with acrylic acid derivatives, in the presence of MnO₂, afforded the 3‐[(5‐bromothiophen‐2‐ylcarbonyl]pyrrolo[2,1‐a]‐isoquinolines 3a , 3b . Suzuki–Miyaura cross‐coupling reactions of the bromides 3a , 3b in aqueous solvent with several activated and deactivated aryl(hetaryl)boronic acids 4a , 4b , 4c , 4d , 4e , 4f using a Pd(II)‐complex under thermal heating as well as microwave‐irradiating conditions afforded the corresponding new arylated pyrrolo[2,1‐a]isoquinoline derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 in high to excellent isolated yields.     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 3, Synthesis of Acetyleno‐Linked Adenosine Dimers

The adenosine‐derived dimers 14a – d and 15b – d have been prepared by coupling the protected 8‐iodoadenosines 3 and 13 with the C(5′)‐ethynylated adenosine derivatives 5 , 6 , 11 , and 12 (Scheme 4). Similarly, the 5′‐epimeric dimer 16 was prepared by coupling 3 with the alkyne 8 (Scheme 5). The propargylic alcohol 4 was transformed into the N‐benzoylated alkyne 5 and into the amine 6 , while the epimeric alcohol 7 was converted to the epimeric amine 8 and the 5′‐deoxy analogues 11 and 12 (Scheme 3). Cross‐coupling of the iodoadenosine 13 with the alkyne 5 to 14a was optimised; it is influenced by the N‐benzoyl and the Et₃SiO group of the alkyne, but hardly by the N‐benzoyl group of the 8‐iodoadenosine. The alkyne is most reactive when it is O‐silylated, but not N‐benzoylated. Cross‐coupling of the 5′‐deoxyalkynes proceeded more slowly. The dimers 14a – d , 15b – d , and 16 were obtained in good yields (Table 2). Deprotection of 14d and 16 led to 18 and 20 , respectively (Scheme 5). The diols 17 and 19 and the hexols 18 and 20 prefer the syn‐conformation in (D₆)DMSO, completely for unit II and ≥80% for unit I; they exhibit partially persistent intramolecular O(5′)−H⋅⋅⋅N(3) H‐bonds. The persistence increases from 18% (unit I of 19 ), 32% (unit II of 17 and 19 ), 45% (unit I of 17 ), 52% (unit II of 18 and 20 ), and 55% (unit I of 20 ) to 82% (unit I of 18 ).     

Design,Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3‐Triazole Derivatives

Here, we demonstrate on the design and synthesis of novel pyrazine containing 1,2,3‐triazole derivatives ( 7a , 7b , 7c , 7d , 8a , 8b , 8c , 8d , and 12a , 12b , 12c , 12d ) using various chemicals, bases, and catalysts synthesized with excellent yields (78–92%) as described in the procedures. The development of this methodology is simple, efficient, and easier to handle; milder reaction conditions and higher selectivity under versatile coupling reagent useful for both amide and ester bond formations have also been developed. The synthesis of amide coupling derivatives prepared by ( 6a , 6b , 6c , 6d ) was coupled with N‐ethylpiperazine to afford ( 7a , 7b , 7c , 7d ) and morpholine to afford ( 8a , 8b , 8c , 8d ) by using 1‐[Bis(dimethylamino)methylene]‐1H‐1,2,3‐triazolo[4,5‐b ]pyridinium 3‐oxid hexafluorophosphate (HATU) and N ,N‐diisopropylethylamine (DIPEA) in dichloromethane at room temperature for 10 h. The derivatives ( 6a , 6b , 6c , 6d ) were coupled with alcohol ( 11 ) by using N ,N′‐dicyclohexylcarbodiimide and 4‐dimethylaminopyridine in dichloromethane (DCM) at room temperature for 16 h to give final compounds ( 12a , 12b , 12c , 12d ). In silico docking approach has been applied to these compounds to screen their efficacy against selected drug targets of cancer and diabetes. The docking approach may facilitate the prediction of activity profile for future experimental findings.     

Structural Identification of DNA Adducts Derived from 3‐Nitrobenzanthrone,a Potent Carcinogen Present in the Atmosphere

3‐Nitrobenzanthrone is a powerful bacterial mutagen and carcinogen to mammals. To obtain precise information on DNA‐adduct formation by 3‐nitrobenzanthrone, a number of DNA adducts, including N‐(2′‐deoxyguanosin‐8‐yl)‐3‐aminobenzanthrone ( 13 a ), 2‐(2′‐deoxyguanosin‐N²‐yl)‐3‐aminobenzanthrone ( 14 a ), N‐(2′‐deoxyadenosin‐8‐yl)‐3‐aminobenzanthrone ( 15 a ), 2‐(2′‐deoxyadenosin‐N⁶‐yl)‐3‐aminobenzanthrone ( 16 a ), and their N‐acetylated counterparts 13 b , 14 b , 15 b , and 16 b were synthesized by palladium‐catalyzed aryl amination of the corresponding nucleoside and bromobenzanthrone derivatives. Among these DNA adducts, DNA adducts 13 a , 13 b , 14 a , 14 b , and 16 a were identified in the reaction mixture of nucleosides (2′‐deoxyguanosine, 2′‐deoxyadenosine, or DNA) with N‐acetoxy‐3‐aminobenzanthrone or N‐acetyl‐N‐acetoxy‐3‐aminobenzanthrone, both of which are recognized as activated metabolites of 3‐nitrobenzanthrone. The formation of these multiple DNA adducts may help explain the potent mutacarcinogenicity of 3‐nitrobenzanthrone.     

A Facile and Efficient Synthesis of 2‐(5‐(4‐Substitutedphenyl)‐4, 5‐dihydro‐3‐phenylpyrazol‐1‐yl)‐6‐Substitutedbenzothiazoles and Their Biological Studies

A series of new 1‐substituted 3, 5‐diarylpyrazolines ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were synthesized in good yield by both conventional and microwave‐assisted synthesis from α, β‐ unsaturated ketones ( 6 , 7 , 8 , 9 ) in n‐butanol and benzothiazole hydrazines ( 2 , 3 , 4 , 5 ). All the new compounds were characterized by IR, NMR, and mass spectral data. The synthesized compounds ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were evaluated for antibacterial and anthelmintic activities. The compounds showed potent anthelmintic activity against earthworm species (Eudrilus eugeniae) and moderate antibacterial activity against bacterial strains such as Gram positive bacteria, Enterococcus faecalis, Staphylococcus aureus, and Bacillus subtilis, and Gram negative bacteria, Escherichia coli and Proteus mirabilis.     

Synthesis and reactions of 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]‐quinazolin‐9‐one and 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one

The reaction of 3‐N‐(2‐mercapto‐4‐oxo‐4H‐quinazolin‐3‐yl)acetamide ( 1 ) with hydrazine hydrate yielded 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 2 ). The reaction of 2 with o‐chlorobenzaldehyde and 2‐hydroxy‐naphthaldehyde gave the corresponding 3‐arylidene amino derivatives 3 and 4 , respectively. Condensation of 2 with 1‐nitroso‐2‐naphthol afforded the corresponding 3‐(2‐hydroxy‐naphthalen‐1‐yl‐diazenyl)‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 5 ), which on subsequent reduction by SnCl₂ and HCl gave the hydrazino derivative 6. Reaction of 2 with phenyl isothiocyanate in refluxing ethanol yielded thiourea derivative 7. Ring closure of 7 subsequently cyclized on refluxing with phencyl bromide, oxalyl dichloride and chloroacetic acid afforded the corresponding thiazolidine derivatives 8, 9 and 10 , respectively. Reaction of 2‐mercapto‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 11 ) with hydrazine hydrate afforded 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 12 ). The reactivity 12 towards carbon disulphide, acetyl acetone and ethyl acetoacetate gave 13, 14 and 15 , respectively. Condensation of 12 with isatin afforded 2‐[N‐(2‐oxo‐1,2‐dihydroindol‐3‐ylidene)hydrazino]‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 16 ). 2‐(4‐Oxo‐3‐phenylamino‐3,4‐dihydroquinazolin‐2‐ylamino)isoindole‐1,3‐dione ( 17 ) was synthesized by the reaction of 12 with phthalic anhydride. All isolated products were confirmed by their ir, ¹H nmr, ¹³C nmr and mass spectra.