Synthesis of pyrazolo [4,5]pyridazine and isoxazolo [3,4d]pyridazine derivatives

Arylhydrazones of diethylacetondicarboxylate3 was treated with formaldehyde to give 1-aryl-4,5,6-trihydropyridaine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4d] 1,3,4,5-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave 1-amidopyrazolo-5-one-1-aryl-3-carboxypyridazine6. On the other hand compound3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-2,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbazide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis of pyrazolo [4,3-c] pyridazine and isoxazolo [3,4-d] pyridazine derivatives

Arylhydrazones of diethyl acetonedicarboxylate3 was treated with formaldehyde to give 1-aryl-1,4,5,6-tetrahyeheypyridazine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4-d] 1,4,5,6-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave pyrazolote [4,3-c] pyridazine6. On the other hand compound 3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-3,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbzide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis of sulphonic acids and sultam derivatives

Reaction of propane-1,3-sultone with amines gave N-substituted aminosulphonic acids2a?i. Dehydration of2a?c with POCl₃ gave the corresponding sultams3a?c. Propane-1,3-sultone1 reacted with tertury amines to give the betaiene salts4–11. 2,4-Dimethyl-1,3-butadiene-1,4-sultone12 condensed with amines to give N-substituted-2,4-dimethyl-1,3-butadiene-1,4-sultams13a and13b. The reaction of3a, 13a with hydrazine hydrate gave acid hydrazides3d or13c. Compounds3d, 13c reacted with isocyanates to yield urea derivatives14a?c, 15a?c.     

Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives

A novel series of fifteen pyrimidine derivatives was prepared from pyrazolobenzothiazine-based chalcones by refluxing with guanidine hydrochloride. The starting materials 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)phenyl)ethanone (2) or 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)benzaldehyde (3) were obtained by N-arylation of 3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-dioxide (1) with 4-fluoroacetophenone or 4-fluorobenzaldehyde, respectively, using phase transfer catalyst, hexadecyl-tri-n-butylphsophonium bromide. The N-arylated product (2) or (3) was reacted in MeONa/MeOH with diversified aromatic aldehydes or ketones to furnish two series of new chalcones 4 and 5. Refluxing of 4 or 5 with guanidine hydrochloride in KOH_(aq) and H₂O₂/EtOH yielded the 2-(4-(2-amino-6-arylpyrimidin-4-yl)phenyl)3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine-5,5-dioxide (6). The structures of chalcones (4 or 5) and corresponding pyrimidines (6) were confirmed with spectral data and elemental analysis. Several chalcones as well as pyrimidines showed marked activity against E. coli and S. aureus.     

Synthesis and characterization of novel benzo[d][1,3]dioxole gathered pyrazole derivatives and their antimicrobial evaluation

Benzo[d][1,3]dioxole gathered pyrazole derivatives (4a–i) were synthesized by the reaction of chalcones with phenyl hydrazine in presence of absolute alcohol as a solvent. Chalcones were prepared by the Claisen-Schmidt reaction between 1-(benzo[d][1,3]dioxol-5-yl)ethanone (2) and substituted aromatic aldehydes. The synthesized compounds were characterized by spectral and elemental analysis data. Furthermore, Benzo[d][1,3]dioxole gathered pyrazole derivatives (4a–i) were evaluated for their in vitro antimicrobial activity. Among the newly synthesized compounds 4a, 4c, 4 g and 4 h showed the excellent antifungal activity and as well as 4a and 4d showed the excellent antibacterial activity when compared to other compounds.     

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.     

Antitumor activity ofPsoralea corylifolia

The activity-oriented fractionation ofPsoralea corylifolia led to an isolation of a (+)-bakuchiol1 as an active principle of its antitumoral propertyin vitro.1 was observed to exhibit a mild cytotoxicity against five kinds of cultured human cancer cell lines,i.e. the A549, SK-OV-3, SK-MEL-2, XF498 and HCT15. The synthesized 2,3-epoxide of (+)-bakuchiol3 showed the similar activity as the (+)-bakuchiol1, whereas the other oxidation derivatives4 and5 including the acetyl-(+)-bakuchiol2 showed a decreased activity.     

Derivatives of Dexanabinol. I. Water-Soluble Salts of Glycinate Esters

Purpose. Glycinate ester-type water soluble derivatives of dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners. Methods. Conventional procedures were used for the synthesis of the novel derivatives. Stability studies in water and blood (rat, dog, human) were performed by HPLC; NMDA receptor binding was determined by radio ligand [³H] MK-801 -displacement; the neuro-protection and neurotoxicity studies were performed in cortical cell cultures. Results. Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl-and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were relatively soluble and stable in water. The quaternary ammonium salt-type derivatives rapidly hydrolyzed to the parent drug in various types of blood including human. In vitro activity studies indicated that the novel derivatives possess NMDA receptor binding properties. The neuroprotecting properties manifested by some of the new derivatives were associated with very low neuronal cell toxicity and are credited to parent compound released by hydrolysis during the experiments rather than to intrinsic activity. Conclusions. Compounds 7 and 8 are promising water-soluble pro-drug candidates for 1; the glycinate ester 3 might be used as an active analog.     

Regioselective synthesis of [1]benzopyrano[4,3-c]pyrazol-4-(1H)-one and [1]benzopyrano[3,4-c]pyrazol-4(3H)-one derivatives

The cycloaddition reaction of N-phenyl-C-cinnamonitrilimine4 to coumarin leads to the formation of 3-styrylbenzopyrano[4,3-c]pyrazole derivative6, whereas 3-phenylsulfonylcoumarin 0163 0181 V 39 or 3-bromocoumarin10 or 3-cyanocoumarin11 gives 1-styrylbenzopyrano[3,4-c]pyrazole derivative7. Also, the cycloaddition of4 to 3-acetylcoumarin15 and 3-benzoylcoumarin16 gives the corresponding dihydropyrano[3,4-c]pyrazole adducts17 and18 respectively. Oxidation of17 and18 gives7.     

Synthesis of imidazole derivatives containing biologically active units

Reaction of oxazolin-5-ones1 withp-amino-diphenylamine was resulted in the formation of the corresponding imidazolin-5-ones2 which on treatment with sulphur afforded phenothiazines3. Acridine derivatives5 were obtained from acetylaminodiphenylamines derivatives6 on heating with ZnCl₂ at 200°C.3 reacted with chloroacetyl chloride to give7 which reacted in turn with different amines to give8. Antibacterial activity of the obtained products was studied.     

New approaches for the synthesis of pyrazole, thiophene, thieno[2,3-b]pyridine, and thiazole derivatives together with their anti-tumor evaluations

The reaction of cyanoacetylhydrazine (1) with acetylchloride (2) gave the N-acyl derivative 3. The latter underwent ready cyclization in sodium ethoxide to give the pyrazole derivative 4 which was the key compound for the synthesis of thiophene, thieno[2,3-b]pyridine, and thiazole derivatives. The anti-tumor evaluations of the newly synthesized products against the three human tumor cell lines, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460), and CNS cancer (SF-268), were studied. Some of these compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference doxorubicin. Molecular modeling of the four compounds 12c, 12f, 16a, and 16d, which showed the maximum inhibitory effect, were done.     

Synthesis and in vitro antiproliferative activity of novel 12(H)-quino[3,4-b][1,4]benzothiazine derivatives

Novel method of N-dealkylating quinobenzothiazinium salts 2, promoted by reaction with benzimidazole, led to a series of new azaphenothiazine derivatives having 12(H)-quino[3,4-b][1,4] benzothiazine 4 structure. Reaction of compounds 4 in an alkaline milieu with alkylating agents occur as N-alkylation of the thiazine nitrogen and yields quinobenzothiazine derivatives 7. In vitro antiproliferative activity of compounds 4 and 7 was tested using two cancer cell lines (SNB-19 and C-32) and cisplatin as a reference. Most of the studied azaphenothiazine derivatives showed activity against both cell lines investigated (5.6–12.4 μg/ml concentration range tested). Compounds 4(b–e) containing a halogen atom or methyl group at the 9-position of the quinobenzothiazine ring show activity in the tested concentration range only against C-32 cell line. Compound 4f with methyl group in 11-position of quinobenzothiazine ring lacked activity against either cell line. The presence of additional aminoalkyl substituents at the thiazine nitrogen atom in compounds 7 increases their activity against both examined cell lines, when compared to compounds 4.     

An improved synthesis of methyl p-hydroxyphenylalkanoates

Friedel-Crafts reaction of isopropoxybenzene with methyl α-chloro-α-(methylthio)acetate1 afforded methyl α-methylthio-p-isopropoxyphenylacetate2d, which was readily converted into methyl p-isopropoxyphenylacetate3 by reductive desulfurization with zinc dust in acetic acid. Methylation of3 with sodium hydride and methyl iodide gave methyl α-(p-isopropoxyphenyl)propionate5. Methyl p-hydroxyphenylalkanoates (4, 6), useful intermediates for some medicines, were easily prepared by treatment of3 and5 with titanium tetrachloride, respectively.     

Synthesis of some heterocycles of potential biological activity

A convenient method for the preparation of imidazobenzimidazole3, imidazoimidazole5, imidazotriazole6 and pyrano [2, 3-c] oxazole7 derivatives is described. This depends on interaction of 2-methyl-4-arylidene-2-oxazolin-5-ones1 with o-diamines, thiosemicarbazide and/or ethylcyanoacetate. The effect of alcoholic potassium cyanide on oxazolinone1 was studied. Antibacterial activity of the obtained products was studied.     

Synthesis of some novel 1,2,4-triazole and 1,3,4-oxadiazole derivatives of biological interest

In this study, a series of novel [1,2,4]-triazolo-[1,3,4]oxadiazole (8), [1,2,4]-triazolo-[1,3,4]oxadiazole thioethers (9a–b), [1,2,4]-triazolo-[1,3,4]oxadiazole arylidines (10a–g), and bis[1,2,4]-triazole (11) derivatives were prepared with the objective of developing better antimicrobial activity. The structures of the compounds were elucidated by spectral analysis. The newly synthesized compounds (8), (9a–b), (10a–g), and (11) were screened for their antimicrobial activity. Among all the tested compounds (10b) shows significant antibacterial activity.     

Cycloaddition reactions of 5-(2-thienyl)methylene derivatives of thiazolidinone-4-thiones and their antimicrobial activities

The cycloaddition of the newely synthesized 5-(2-thienyl)methylene derivatives of thiazolidinone-4-thiones,2a?c to acrylonitrile (3a), ethyl acrylate (3b), N-phenylmaleimide (6) and dimethyl fumarate (8) has been evaluated. Under thermal reaction conditions [4+2] cycloaddition proceeds with complete site and regioselectivity to yield the cycloadduct,4, 5, 7 and9, respectively. The antimicrobial activities of some of the new products were tested.     

Synthesis of 7-[p-(methylthio)benzoyl]-5-benzofuranacetic acid

A new method was described for the preparation of 7-[p-(methylthio)benzoyl]-5-benzofuranacetic acid6, which is an analgesic agent. Methyl 5-(2,3-di-hydrobenzofuran)acetate3 was obtained by Friedel-Crafts reaction of 2,3-dihydrobenzofuran with methyl α-chloro-α-(methylthio)actate1 and desulfurization of2. Tifurac6 was synthesized from acylation of 3 with p-(methylthio)benzoyl chloride followed by bromination of4, dehydrohalogenation, and hydrolysis of5.     

Synthesis and structure evaluation of new complex butylarylpiperazin-1-yl derivatives

A series of arylpiperazine derivatives of 1,16-diphenyl-19-azahexacyclo-[14.5.1.0^2,15.0^3,8.0^9,14.0^17,21]docosa-2,3,5,7,8,9,11,13,14-nonaene-18,20,22-trione and 4,10-diphenyl-1H,2H,3H,5H-indeno[1,2-f]isoindole-1,3,5-trione was synthesized. The pharmacological profile of compound 4 at the 5-HT_1A receptor was measured by binding assay. The title compounds were tested in cell-based assay against the human immunodeficiency virus type-1. The X-ray crystallographic studies of derivatives 2, 6, 7, 11, 19, and 20 were presented.     

Synthesis of some new indolo[2,3-c]isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities

A new series of novel compounds [10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]carbohydrazides (3a–c), 1-[10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]fomyl-, -3′,5′-dimethylpyrazoles (4a–c), -3′,5′-diphenylpyrazoles (5a–c), -3′-methylpyrazol-5′-ones (6a–c) and -1′,3′,4′-oxidiazole-2′-thiones (7a–c) linked to indoloisoquinoline at position-6 through formyl bridge was prepared. The structures of these newly synthesized compounds were confirmed by their spectral studies and elemental analysis. These compounds have been screened for their antimicrobial and antioxidant activities. Compounds 4a, 4b, 5a, 5b, 5c, 6b, 7a, and 7c exhibited the maximum zone of inhibition against A. niger, A. flavus, and A. fumigatus. Compounds 4a, 5a, 5c, 6b, 6c, 7a, and 7b showed good antibacterial activity. Compounds 4b, 4c, 5b, 5c, 6a, 6b, 7a, 7b, and 7c showed good radical scavenging activity compared with standards.     

Synthesis of pyranochromene and pyranopyrimidine derivatives from substituted natural coumarin isolated from Ammi majus L. and their biological evaluation

A series of novel coumarin derivatives were synthesized from 6-hydroxy-7-methoxy-4-methyl coumarin which was isolated from the aerial parts of the Egyptian medicinal plant Ammi majus L. (Apiaceae). The key intermediate 3-amino-5-methoxy-1-(4-methoxyphenyl)-10-methyl-8-oxo-1,8-dihydropyrano[3,2-f]chromene-2-carbonitrile (3c) was obtained in one-pot synthesis by treating α-cyanocinnamonitrile (1-c) with the natural compound: 6-hydroxy-7-methoxy-4-methyl coumarin (2). Chemical, elemental and spectroscopic evidences confirmed the structures of the synthesized compounds. Some of the newly synthesized compounds exhibited better anti-inflammatory activities at low concentrations compared with indomethacin as positive control.