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.     

The Knoevenagel reaction of malononitrile with acetylacetone: New route of pyrazole,pyrazolo[2,3-C]pyridine,benzene, pyridazine and benzo[C]pyridazine derivatives

The Knoevenagal reaction of malononitrile and acetylacetonegave the acyclic product 3 whichwas separated in a good yield and identified. The reactivity of 3 towards some chemical reagents is studied. Thus, the reaction of 3 with aromatic aldehydes, hydrazines and cyanomethylene derivativesgave products 6–12. Reaction of 3 with benzenediazonium chloridegave the primidine derivative 14.     

New synthesis of chromonopyrroloimidazolinones and arylidene thioxoimidazolinones

6-Formyl-5-methoxy-2-methyl chromone derivatives condensed with 2-thiox-4-imidazolinone derivatives to form the corresponding “10-methoxy-7-methyl-3-thioxochromono [6,7-b]pyrrolo[1,2-a-]-imidazolin-1-one derivatives(IIIa-f) or the 5-arylidene-2-thioxo-4-imidazolinone derivatives(IVa-f). The activity of the NH in the imidazol moiety of(IIIa) was confirmed by formation of the Mannich bases(Va, b). Moreover, alkylation of(IIIa) was undertaken to give the alkylmercapto derivatives(VIa, b). The antimicrobial activities of compoundsIIIb-e, IVa, IVd andIVe 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.     

Thienobenzothiopyranones III new 4H-thieno[2,3-b][1]benzothiopyran-4-ones carrying different heterocyclic moieties of expected pharmacological interest

Reaction of 2-formyl-4H-thieno[2,3-b][1]benzothiopyran-4-one (1) with different heterocyclic amines afforded the corresponding Schiff's bases (2–4). Diethyl malonate, ethyl cyanoacetate and malononitrile were reacted with1 to afford compounds5,7 and8, respectively. Compound5 was cyclized to the pyrazolidin-3,4-dione (6) by the action of hydrazine hydrate, whereas compound7 was utilized for the synthesis of the thiazolin-4-one derivatives (9–13).     

Synthesis of 3-amino-1,4-dihydropyridine derivativevia an intramolecular rearrangement of 1,4-dihydropyridine-3-hydroxamate

2,6-Dimethyl-4-(3′-nitrophenyl)-3-methoxylaminocarbonyl-1,4-dihydropyridine-5-carboxylic acid methylester,3b reacted with 2-cyanoethanol or benzylalcohol to give the corresponding cyanoethylurethane compound6c in 40.6% yield and benzylurethane compound6d in 32% yield. The cyanoethylurethane6c was hydrolized in ethanolic NaOH to give 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-amino-5-carboxylic acid 5-methyl ester. HCl8 in 64.8% yield. Another acid hydrolysis of benzylurethane6d gave 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-amino-5-carboxylic acid 5-methylester. HBr11 in 54.7% yield.     

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 and antitumor studies of novel benzopyrano-1,2,3-selenadiazole and spiro[benzopyrano]-1,3,4-thiadiazoline derivatives

A convenient and efficient synthetic protocol of new selenadiazole and thiadiazoline derivatives incorporating benzopyranone moiety from readily available starting materials was described. Reaction of different 2,2-dialkyl and 2,2-spirocycloalkyl dihydrobenzopyranones 1a–e with semicarbazide hydrochloride and thiosemicarbazide afforded the corresponding semicarbazones 2a–e and thiosemicarbazones 3a–e, respectively. Furthermore, cyclization of the semicarbazones 2a–e via oxidation using selenium dioxide gave a novel series of chromenoselenadiazoles 4a–e. A series of spirobenzopyrano-1,3,4-thiadidazolines 5a–e were synthesized by refluxing of the thiosemicarbazones 3a–e in acetic anhydride. The synthesized compounds were tested in vitro against four cancer cell lines namely: MCF-7, VERO, WI-38, and HEPG-2. In vivo studies were also performed using Ehrlich ascites carcinoma for antitumor activity. Interestingly, Compounds 4b and 5a showed significant antitumor activities and were capable to improve the hematological parameters as well as increase the mean survival time of the mice bearing tumor.     

Synthesis of potential anticancer derivatives of pyrido[1,2-a]benzimidazoles

In this study, the starting compounds, 2-cyanomethyl benzimidazoles (1 or 2) were reacted with ethyl acetoacetate, ethyl benzoylacetate, or 2-acetylbutyrolactone to give the novel series of 4-cyano-3-substituted-1-oxo-1H, 5H-pyrido[1,2-a]benzimidazole (3–6, 15, 16). The latter was chlorinated to give compounds 7–10, 17, 18 then aminated with 4-(2-fluorophenyl) piperazine to afford compounds 11–14, 19, 20. The structures of the new compounds were confirmed by elemental analysis as well as ¹H-NMR, IR, and mass data. All the synthesized products were subjected to in vitro anticancer screening that revealed that all the tested compounds exhibited antitumor activity against human breast adenocarcinoma (MCF7) cell line, with IC₅₀’s 3.43–14.70?μg/ml.     

Design, synthesis, antimicrobial, anti-inflammatory, and analgesic activity of novel dihydrobenzo furo[3,2-e]isoxazolo[4,5-b]azepin-5(5aH)-ones

Novel series of dihydro benzofuro[3,2-e]isoxazolo[4,5-b]azepin-5(5aH)-ones 6 have been synthesized from 3,5-dimethyl-4-nitroisoxazole 1. Compound 1 on treatment with salicyl aldehydes afforded the corresponding nitrostyrylisoxazoles 3, which upon reaction with ethyl bromo acetate followed by cyclization with triethylamine furnished ethyl 2,3-dihydro-3-[(3-methyl-4-nitro-5-isoxazolyl)methyl]benzofuran-2-carboxylates 5. Reductive cyclization of compounds 5 was effected with SnCl₂–MeOH to give the title compounds 6. Compounds 4–6 were characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral data. The title compounds 6a–g were evaluated for their antimicrobial, anti-inflammatory, LOX-5 inhibitory, and analgesic activity. Compounds 6b and 6c exhibited significant antimicrobial activity, potent anti-inflammatory and analgesic activities as that of standard drugs.     

Reactions with hydrazidoyl halides VIII: Synthesis of thiazolo [3,2-a] benzimidazoles,imidazo[2,1-b] thiazoles and imidazo[2,1-b] benzthiazoles

Hydrazidoyl halides were condensed with 2-mercaptobenzimidazole2 yielding4a-c which were cyclized to the corresponding 3-substituted 2-arylazothiazolo-[3,2-a] benzimidazole6a-c, respectively. Imidazo-[2,1-b] thiazoles9, 12, 15, and16 were obtained by the reaction of hydrazidoyl halides1 with 2-mercapto 4,5-dihydroimidazole3 and 2-aminothiazoles10. The structures of the products were established on the basis of their elemental analysis and spectral data studies.     

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.     

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 antitumor evaluation of α-methylene-γ-butyrolactone-linked to 5-Substituted uracil nucleic acid bases

Six, heretofore undescribed, 5′-Methyl-5′-(5-Substituted uracil-1-ylmethyl)-2′-oxo-3′-methylenetetrahydrofurans (F, Cl, Br, I, CH₃, H) (6a-f) were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone bearing 5-substituted uracils (6a-f), the efficient Reformatsky type reaction was employed which involves the treatment of ethyl α-(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of K₂CO₃ (or NaH). These lactone compounds6a-f exhibited moderate to significant activity in all of the three cell lines, and6b, 6c and6e showed significant antitumor activities (inhibitory concentrations (IC₅₀) ranged from 1.3–3.8 μg/ml).     

Synthesis and biological evaluation of benzo[d]imidazolyl chromeno[2,3-d]pyrimidinones

A series of benzo[d]imidazolyl chromeno[2,3-d]pyrimidnones were described. The key intermediate 2-cyano-N-(2-mercapto-1H-benzo[d]imidazol-5-yl)acetamide (3) is obtained by reacting 5-amino-2-mercaptobenzimidazole (1) with ethyl cyanoacetate (2). Compound 3 on reaction with substituted salicylaldehydes afforded 2-imino-N-(2-mercapto-1H-benzo[d]imidazol-5-yl)-2H-chromene-3-carboxamides (5) in good yields. Compounds 5 on condensation with formalin furnished the title compounds viz., 3-(2-mercapto-1H-benzo[d]imidazol-5-yl)-2H-chromeno[2,3-d]pyrimidin-4(3H)-ones (7). All the synthesized compounds were screened for their anti-microbial and anti-oxidant activities.     

Synthesis and antitumor activity of new pyrido[2,3-d]pyrimidine derivatives

New series of pyrido[2,3-d]pyrimidines such as; 5-(4-aryl-5-sulfanyl-4H-[1,2,4]triazol-3-yl) 1H,3H,8H-pyrido[2,3-d]pyrimidine-2,4,7-triones 6, 7; S-[3-(2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)-4-(4-substituted phenyl)-4H-[1,2,4]triazol-5-yl]-2-(4-phenylpiperazin-1-yl)ethanethioates 10, 11; 2,4,7-trioxo-N′-[(4-substituted piperazin-1-yl)acetyl]-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 13–16 and N′-arylidene-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 17–19 was synthesized through the reaction of the key intermediate 2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazide 3 with different reagents. The structures of the newly synthesized compounds were elucidated through microanalysis, IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds have been subjected to in vitro antitumor evaluation by bleomycin-dependant DNA damage assay. The most active antitumor compound 6 was selected for further in vivo evaluation of antineoplastic activity against Ehrlich ascites carcinoma in mice. It was observed that our target compound has a potent antitumor activity.     

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.     

Reactions with halogenated compound: Synthesis of several new pyrazolo[3,2-c] triazine and 2-benzenesulfonylglyoxal arylhydrazone derivatives

Diazotized primary artomatic amines4 coupled with the ketosulfones1–3 in ethanol in the presence of sodium acetate at 0°C to afford the corresponding hydrazones5–7. Also diazotized 3-aminopyrazoles14 coupled with1–3 in ethanolic sodium acetate to give the pyrazolotriazines18–20 in good yields. Compounds5–7 and18 can also be obtained from the reaction of hydrazidoyl halides8–10 and21 with sodium benzenesulfinate. The hydrazones11–13 can easy be oxidized to the hydrazones5–7, using hydrogen peroxide in acetic acid.     

Synthesis and biological evaluation of some novel urea and thiourea derivatives of isoxazolo[4,5-d]pyridazine and structurally related thiazolo[4,5-d]pyridazine as antimicrobial agents

This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7-dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c–d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl)-benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H-thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study.     

Synthesis of azabicyclo[4.2.0]octa-1,3,5-trien-8-one analogues of 1H-imidazo[4,5-c]quinoline and evaluation of their antimicrobial and anticancer activities

In search of new and efficient antimicrobial and anticancer agents based on the imidazoquinoline structural framework, a series of novel 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-ones (8a–f) were synthesized from the corresponding 2,4-dihydroxoquinoline derivative through multistep reactions. The structures of these compounds were established by IR, ¹H NMR, ¹³C NMR and mass spectral studies. The 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-one (8a–f) analogues were evaluated for their in vitro antimicrobial activity by serial dilution method minimum inhibitory concentration (MIC). The derivatives 8c, 8e and 8f exhibited excellent antibacterial activity comparable to the parent drug ampicillin with MIC value. Compounds 7a–f and 8a–f were also assessed for their cytotoxic activity (IC₅₀) against HeLa cells using the Trypan blue exclusion assay method. The compounds 7c and 8b displayed potential anticancer activity. In a molecular docking study, these compounds showed minimum binding energy and good affinity towards the active pocket. They are believed to be good inhibitors of β-tubulin. The results of these studies provided evidence that 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-one (8a–f) derivatives are a promising class of antibacterial and anticancer agents.