Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.     

Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives with potential analgesic and anti-inflammatory activity

A series of novel N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide derivatives was synthesized and evaluated for analgesic and anti-inflammatory activity. In this study, biphenyl-4-carboxylic acid hydrazide was converted to the corresponding aryl hydrazones using aryl aldehydes in the presence of catalytic amount of glacial acetic acid. The aryl hydrazones on reaction with thioglycolic acid in the presence of anhydrous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide which further on reaction with aromatic aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid furnished the title compounds. All compound exhibited anti-inflammatory activity at the dose 10?mg/kg. The structures of all these newly synthesized compounds were confirmed by their elemental analyses (C, H, N) and spectral data (IR and ¹H NMR).     

Synthesis of some new hydrazide-hydrazones, thiosemicarbazides, thiadiazoles, triazoles and their derivatives as possible antimicrobials

The title compounds were prepared by reacting [(4,5-diphenyl-1H-imidazol-2-yl)thio]acetic acid hydrazides 6 and 7 with aromatic aldehydes to give the corresponding hydrazones 6a-m and 7a-d or with isothiocyanates to afford the corresponding thiosemicarbazides 8a-c and 9. 8a-c and 9 were cyclized into triazoline-5-thiones 10a-c and 11 in the presence of sodium hydroxide or into 1,3,4-thiadiazoles 14a-c and 15 in the presence of sulfuric acid. On the other hand, 10c and 11 were also reacted with alkyl halides to obtain their thioether derivatives, 12a,b and 13. All the synthesized compounds were characterized by their elementary analysis and by using UV, IR, NMR and mass spectrometry. 6b, c, f, h-k, m, 7, 7d, 8c, 9, 10c, 11, 12a-b, 13, 14 and 15 were tested for antimicrobial activity, but no significant activity was observed.     

Synthesis of 6-exomethylenepenams as β-lactamase inhibitors

The 6,6-dibromopenam (6) was treated with CH3MgBr and carbaldehyde 5 to afford the hydroxy compound 7, which was reacted with acetic anhydride to give acetoxy compound 8. The deacetobromination of 8 with zinc and acetic acid gave 6-exomethylenepenams, E-isomer 10 and Z-isomer 9, which was oxidized to sulfone 11 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl3 and neutralized to give the sodium salts 12, 13 and 14.     

Synthesis,antiinflammatory and analgesic activity of new hexahydropyrimidine derivatives

A number of potentially active hexahydropyrimidine derivatives of pharmaceutical interest have been synthesized. Various diSchiff's bases prepared by reacting different aromatic aldehydes with 1,3-diaminopropane were suitably reduced to give their tetrahydro derivatives which were then condensed with appropriate aldehydes to give a series of hitherto unreported hexahydropyrimidines. The resulting products were evaluated by oral route for their antiinflammatory activity. The activity of compounds 11, 23 and 4 was excellent and comparable to indomethacin. In addition to oral route of administration, the antiinflammatory activity of hexahydropyrimidine derivatives was also studied topically through transdermal gels. Compounds 11, 23, 4 and 22 produced significant inhibition in edema and showed good antiinflammatory activity comparable to diclofenac sodium gel (Relaxyl gel). All these compounds were also tested for their analgesic activity and their LD50 determined. Compounds 11, 20 and 23 showed a comparable activity with aspirin. The MTD for all the compounds was found to be > 1800 mg/kg.     

Synthesis of new quinoline derivatives as antimicrobial agents

2-Hydroxyquinoline-4-hydrazide was condensed with some aromatic aldehydes and acetophenones to give the hydrazones 1a-h. It was also reacted with HCOOH, PhCOCl and p-CH3O-PhCOCl to afford 2a-c. Cyclization of 2b was completed by using PPA, POCl3 and/or P2S5, which gave compounds 3, 4, and 6 respectively. Reaction of 4 with some amines gave the corresponding derivatives 5a-f. The thiosemicarbazide 7 was cyclized under acid and basic condition to give the thiadiazolyl-8 and triazolyl-10 derivatives.     

A novel synthesis of heterocyclic compounds containing coumarin moiety of potential antimicrobial activity

The chemical behaviours of 4-methyl-2-oxo-2H-benzopyran-7-yl oxoacetyl hydrazine (2) towards some different reagents such as anhydride compounds, aromatic aldehydes, carbon disulphide, and nitrous acid yielded the corresponding pathalazine derivatives (3, 4, 5), hydrazone derivative (6), 1,3,4-oxadiazole derivative (7, 8, 9) and acid azide (10) respectively. Treatment of10 with absolute alcohols, amines and ethyl amino acid ester gave the corresponding carbamate derivative (11), substituted urea derivative (12) and ethyl substituted alkyl acetate (13) respectively. The biological activity of some synthesized compounds was evaluated.     

Design and synthesis of some new thiazolo [3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen as anti-inflammatory and analgesic agents

In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.     

Synthesis of new 2-thiouracil-5-sulfonamide derivatives with biological activity

2-Thiouracil-5-sulfonylchloride 1 reacted with a series of aromatic and heterocyclic amines to give 2a-j. The same compound 1 was reacted with a series of sulphonamides giving different sulphonamides of type 3a-e. On the other hand compound 1 was allowed to react with p-aminoacetophenone givining compound 4 which in turn was allowed to react with derivatives of alkyl thiosemicarbazides to give thiosemicarbazones of type 5a-e, also compound 4 was monobrominated to give compound 6 which in turn was reacted thiosemicarbazones of some aldehydes to give the corresponding thiazole derivatives 7a-f. In the same time compound 4 was reacted with a series of aromatic and heterocyclic aldehydes givining chalcones 8a-g (Claisen-Schemidt reaction). Also compound 4 was allowed to react with a series of aromatic and heterocyclic aldehydes, ethyl cyano acetate and/or malononitrile, and ammonium acetate giving pyridine derivatives 9a-d and 10a-e respectively. The biological effects of some of the new synthesized compounds was also investigated.     

Synthesis and biological properties of 2-hydroxy-1-(1-phenyltetralyl)piperidine and some of its intermediates as derivatives of phencyclidine

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP) has shown analgesic effects. Some of its derivatives were synthesized and their biological properties were studied. To date, only saturated ketones have been used as starting materials for synthesizing the phencyclidine family. In order to show desirable biological activity, the aromatic and piperidine rings are necessary for these compounds. Using alpha-tetralone as a starting material, 2-hydroxy-1-(-phenyltetralyl)piperidine, an analogue of the phencyclidine family, and some of its intermediates were synthesized. This ketone was reacted with phenyl magnesium bromide and the resultant alcohol was reacted with acetic anhydride to give alkene that was treated with potassium permanganate to give diol. This compound was treated with a suspension of sodium azide and trichloroacetic acid to give the azide compound that was reduced with LiAlH4 to give the primary amine. Cyclization of this compound with 1,5-dibromopentane finally gave a tertiary amine. It is predicted that the title compound 2-hydroxy-1-(1-phenyltetralyl)piperidine exerts a potent analgesic effect on acute and phasic pain.     

Novel analogues of sydnone: synthesis, characterization and antibacterial evaluation

New sydnone derivatives bearing a substituted phenyl ring at the 3-position have been synthesized. Two separate series of 3-(carboxyphenyl)sydnone derivatives have been prepared by cyclization of the corresponding N-nitroso-N-(carboxyphenyl)-glycine 3. The obtained 3-(carboxyphenyl)sydnones 4 were subjected to a series of different chemical reactions on the carboxylic acid group. Compound 5, the potassium salt of 4a, was reacted with alpha-chloroacetanilide derivatives 6 to give the corresponding esters 7. On the other hand, the acid hydrazide 9 was condensed with different aromatic aldehydes to give the corresponding arylidene derivatives 10. The synthesized compounds were tested for their antibacterial activities against both gram-positive and gram-negative organisms. Some of the test compounds exhibited high activity; among them, 10d is considered to be a lead compound possessing high broad-spectrum antibacterial activity.     

Synthesis of some indole derivatives with potential antiinflammatory activity

2-Methylindole-3-acethydrazide (1) was reacted with arylisothiocyanate to give the corresponding 4-arylthiosemicarbazides 2a-d. Cyclization of the latter gave the corresponding 3-mercapto-5-[3-(2-methylindolyl)methyl]-1,2,4-triazoles 3a-d. Compounds 3a-c reacted with chloroacetic acid to give the corresponding indolyl-1,2,4-triazolythioglycolic acids 4a-c. The methylmercapto derivative 5 was also obtained from 3a and methyliodide. The hydrazide 1 was also reacted with carbon disulfide to give the corresponding indolymethyl-1,3,4-oxadiazole-2-thione (6) which was condensed with piperidine and formaldehyde to give the corresponding Mannich base 7. Condensation of 1 with aromatic aldehydes gave the corresponding hydrazones 8a-c which were converted into the corresponding oxadiazolines 9a-c.     

Synthesis of new 2-thiouracil-5-sulphonamide derivatives with antibacterial and antifungal activity

2-Thiouracil-5-sulphonic acid N-(4-acetylphenyl) Amide (1) was reacted with a series of aromatic aldehydes giving chalcones 2 (Claisen-Schemidt reaction), some of these chalcones were reacted with urea and thiourea giving pyrimidine-2-one and pyrimidine-2 thione derivatives respectively of the type 3a,b and 4a,b. In addition many chalcones were reacted with hydroxylamine hydrochloride giving isoxazoline derivatives 5a,b. They could also reacted with phenylhydrazine to give pyrazoline derivatives 6a,b, chalcones also were reacted withethylcyano acetate and/or malononitryl in pyridine giving pyran derivatives 7a,c and 8a,c. In another pathway chalcones were epoxidised by H2O2 giving epoxides 9a,c which in turn were reacted with phenylhydrazine giving 4-hydroxypyrazoline derivatives 10a,c. In another reaction chalcones were reacted with ethylcyanoacetate in presence of amm.acetate giving pyridone derivatives 11a,d which could be prepared also in exellent yield from compound 1 by its reaction with certain aromatic aldehydes and ethylcyanoacetate in presence of ammonium acetate. Finally, compound 1 was reacted with semicarbazide giving semicarbazone intermediate 12 which in turn was reacted with thionyl chloride giving thiadiazole derivative 13. The biological effects of some of the new synthesized compounds were also investigated.     

Novel benzimidazole derivatives as expected anticancer agents

A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1-methyl analogues 2c-h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, carbon disulfide and/or thiosemicarbazide to yield compounds 11-19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiff's bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly synthesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocytoma of the rat adrenal medulla) cells. Benzimidazole-2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells.     

DNA binding,antiviral activities and cytotoxicity of new furochromone and benzofuran derivatives

Bromination of visnagin (1) afforded 9-bromovisnagin (2) which on its alkaline hydrolysis afforded the 3-acetyl benzofuran derivative (3). The condensation of (3) with hydrazine hydrate, phenylhydrazine and/or hydroxylamine hydrochloride afforded the corresponding pyrazole derivatives (4a, b) and isoxazole derivative (4c). On the other hand, when compound 3 was condensed with some aromatic aldehydes, this yielded corresponding α, β-unsaturated keto derivatives (5a–e). Furthermore, when 1 was subjected to chlorosulfonation, the visnaginsulfonylchloride derivative 6 was afforded, which on amidation using morpholine, a sulonamido derivative (7) was obtained. Alkaline hydrolysis of the latter compound yielded 7-N-morpholinosulsamidobenzofuran (8) which was condensed with some aromatic aldehydes to yield the corresponding chalcone compounds (9a–e). Demethylation of visnagin afforded norvisnagin (10). The reaction of 10 with ethylbromoacetate in dry acetone yielded the ester benzopyran derivative (11) which reacted with hydrazine hydrate to afford the corresponding hydrazide derivative (12) and this was condensed with 3,4,5-trimethoxybenzaldehyde to give the corresponding hydrazone (13). A thaizolidinone derivative (14) was obtained by condensation of (13) with thioglycolic acid. Chloromethylation of norvisnagin afforded a 4-chloromethyl derivative (15) which reacted with different primary and secondary amines to yield the corresponding ethylamino derivative (16a, b). Moreover, mannich bases (16a, b) and (17a–c) were obtained by reacting norvisnagin with different primary and secondary amines in the presence of formalin but benzoylation of (16a, b) and (17a–c) afforded 4-oxybenzoyl derivative (18a–e). The prepared compounds were tested for their interaction with DNA; bromovisnagin 2 showed the highest affinity and compounds 6, 15, 8a, > 14, > 16b, 17a, and 16a showed moderate activity in decreasing potency. Moreover, compound 2 also was the most active as antiviral agent toward HS-I virus and compounds 6, 7, 15, 14, 16a, and 18a were found to be moderately active. CD₅₀ of the active compounds were also measured.     

Synthesis and antimicrobial activity of some new 2,5-imidazolidinediones

1,3-Diphenyl-4-thione-2,5-imidazolidinedione (3) was reacted with amino compounds and o-diamines to give 1,3-diphenyl-4-substituted imino-2,5-imidazolinediones (4a-m) and 1,3-diphenyl-1H-imidazo[4,5-b]quinoxaline-2(3H)-ones (5a-c), respectively. Condensation of 3 with hydrazines afforded the corresponding hydrazone derivatives (6a-c). Reaction of 6a with acetyl chloride, aromatic aldehydes, arylsulphonyl chlorides, phthalic acid anhydrides and isocyanates or thiocyanates furnished 6d, furnished the acetyl-amido derivative 6b, the benzylidenimino derivatives 7a-d, the arylsulphonamido derivatives 8a-b, the phthalimido derivatives 9a-b and the ureido and thioureido derivatives 10a-b, respectively. Again compound 3 was reacted with n-butylmagnesium bromide or diazomethane to give the dibutyl derivative 12 or 13.     

Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as promising 5alpha-reductase inhibitors

Condensation of 3beta-hydroxy-16-[(4-chlorophenyl)methylene]androst-5-en-17-one (1) with hydrazine hydrate in acetic acid afforded N-acetyl pyrazoline derivative 2, while condensation of 1 with semicarbazide afforded compound 3. Also, compound 1 was treated with hydrazine hydrate in absolute methanol or ethanol to afford the corresponding alpha-methoxy (4) and alpha-ethoxy (5) derivatives, which were cyclized with etherated boron trifluoride to the pyrazoline derivative 6. The latter could be prepared directly by refluxing 1 with hydrazine hydrate in dioxane. Oxidation of compound 6 with Oppenour or Moffat oxidizing agents yielded 3-oxo-derivatives 7 and 8, respectively. On the other hand, condensation of compound 1 with substituted hydrazines, gave the corresponding 3beta-hydroxyandrostenopyrazolines 9a,b, which were oxidized using the Moffat method to give 3-oxo-androstenopyrazolines 10a,b, which were condensed with ethylene triphenyl-phosphorane in DMSO to yield 3-ethylene androstenopyrazolines 11a,b. Dehydrogenation of 9a,b with Wettestein oxidation afforded Delta4,6-diene-3-one analogues 12a,b, which were treated with chloranil to yield Delta(4,6,8(14))-tri-ene-3-one analogues 13a,b. Oppenour oxidation of 9a,b afforded Delta4-ene-3-one analogues 14a,b, which were treated with dichlorodicyanoquinone (DDQ) in dioxane to give Delta1,4,6-triene-3-one analogues 15a,b. Pharmacological screening showed that many of these compounds inhibit 5alpha-reductase activity.     

Synthesis of new pyrimidine derivatives with evaluation of their anti-inflammatory and analgesic activities

5-Formyl-6-aminopyrimidine-2,4-(1H, 3H)-dione (2) has been previously prepared fromcompound 1. Cyclocondensation reaction of compound 2 with cyanoacetamide gave substituted pyridopyrimidine 3. Also, compound 2 was condensed with p-amino acetophenone and hydrazine derivatives to give 5-([(4-acetylphenyl)imino]methyl)-6-aminopyrimidine (4) and 5-substituted carboaldehyde-6-amino pyrimidine derivatives (5a-d), respectively. Moreover, cyclocondensation reaction of compound 2 with thiosemcarbazide and semicarbazide hydrochloride gave 5-(5-thioxo or oxo-triazol-3-yl)-6-amino pyrimidine (6) and (7), respectively. Cyclocondensation reaction of compound 2 with thiourea and ethyl acetoacetate led to the formation of substituted ethyl bipyrimidine-5-carboxylate 8. Also, compound 2 was reacted with acetoacetic acid hydrazide and 2-cyanoacetohydrazide to give 5-(acetylpyrazol-6-aminopyrimidine 9 and 3-(6-aminopyrimidine-5-yl) pyrazole-4-carboxamide 10, respectively. Furthermore, compound 1 was diazotized to afford the diazonium salt 11. Its coupling with ethyl acetoacetate, ethyl cyanoacetate, acetylacetone, malononitrile, cyanoacetamide, diethylmalonate, in sodium acetate buffered solution afforded substituted hydrazonopyrimidines: ethylhydrazono-3-oxobutanoate 12, ethylhydrazono-3-oxopropanoate 13, pentane-2,3,4-trione hydrazone 14, cyanohydrazonoacetamide 15, diazenyl malonamide 16 and diethylhydrazonomalonate 17, respectively. Moreover, substituted pyrazolediazenylpyrimidine derivatives 18a,b, 19a,b, 20, 21a-c, 22 were synthesized by the cyclization of substituted hydrazonopyrimidines 12, 17, 15, 14 and 13, respectively. The analgesic and anti-inflammatory activities of some of the synthesized compounds were evaluated. Compounds C18a, C20, C21b and C22 showed the most significant analgesic effects among synthesized moieties. All tested compounds, nonetheless, C18b showed significant anti-inflammatory effect in carrageenan induced paw edema model.     

Synthesis and molluscicidal activity of new chromene and pyrano[2,3-c]pyrazole derivatives

The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and dimedone 11a, b to afford the 4(3-indolyl)-chromene derivatives 12a, b respectively, and with the pyrazolone derivatives 13a-d to afford the arylidene exchange derivatives 14a-c and the pyranopyrazole derivative 15, respectively. The arylidene derivatives 10a, b react also with indane-1,3-dione 16 to afford the arylidene exchange derivatives 18a, b. The molluscicidal activity of the synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated and most of them showed weak to moderate activity.     

Synthesis, anticonvulsant and neurotoxicity screening of some novel 1,2,4-trisubstituted-1H-imidazole derivatives

A series of 1,2,4-trisubstituted-1H- imidazole derivatives (4a-o) was synthesized by reacting 2,4-disubstituted-1H-imidazoles (3a-o) with chlorobenzene in the presence of triethylamine. Phenylglyoxal (2) was reacted with different aromatic aldehydes in the presence of ammonium acetate and glacial acetic acid to afford the disubstituted imidazoles (3a-o). The structures of the synthesized compounds were confirmed on the basis of their elemental analysis and spectral data results. Anticonvulsant activity was shown by majority of the synthesized compounds in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens when given i.p. to mice. In anticonvulsant screening, only one compound 4k showed potent activity comparable to that of standard drugs phenytoin and carbamazepine. Compounds 4a, 4c, 4e, 41 and 4n passed the rotorod test successfully without any sign of neurological deficit.