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 of 4-(2-thiazolyloxy)phenylalkanoic acids as an antiinflammatory agent

The efficient synthesis of 4-(2-thiazolyloxy)phenylalkanoic acids (10a-c), which are a potent antiinflammatory agent, was achieved in 5～6 steps starting from isopropoxybenzene and methyl α-chloro-α-(methylthio)acetate (1). The key intermediate (4) was prepared by Friedel-Crafts reaction of isopropoxybenzene with (1) followed by desulfurization and the removal of isopropyl protector. Methyl 4-hydroxyphenylalkanoates (6,8) were similarly obtained from alkylation of (3) and deprotection.     

Synthesis of hexaprofen [2-(4-cyclohexylphenyl) propionic acid]

A novel preparative method for hexaprofen, which is a potent antiinflammatory agent, is described. Friedel-Crafts reaction of cyclohexylbenzene with ethyl α-chloro-α-(methylthio) acetate1 and α-chloro-α-(methylthio) acetonitrile2 afforded ethyl 2-(methylthio)-2-(4-cyclohexylphenyl) acetate7 and 2-methylthio-2-(4-cyclohexylphenyl) acetonitrile8, respectively. Compounds7 and8 were converted into the corresponding ethyl 2-methylthio-2-(4-cyclohexylphenyl) propionate9 and 2-methylthio-2-(4-cyclohexylphenyl) propionitrile10 by methylation with sodium hydride and methyl iodide. Hexaprofen13 was prepared by hydrolysis of ethyl 2-(4-cyclohexylphenyl) propionate11 and of 2-(4-cyclohexylphenyl) propionitrile12 followed by desulfurization of compounds9 and10.     

Synthesis and antimicrobial activities of some isoxazolyl thiazolyl pyrazoles

A series of isoxazolyl thiazolyl pyrazoles 5a–d was synthesized by multi-step process, starting from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid, DHAA) 1. DHAA 1 was easily converted to thiosemicarbazone 2 which on reaction with α-bromoketones yielded thiazolyl hydrazones 3. Refluxing 3 in ethanol-acetic acid furnished 1-(5-hydroxy-3-methyl-1-substituted pyrazol-4-yl)-1,3-butanediones 4. Finally, the title compounds 5a–d were synthesized from 4 on treatment with hydroxylamine. The in vitro antimicrobial activity of compounds 3a–d, 4a–d and 5a–d were tested. Most of the synthesized compounds exhibited significant antibacterial and antifungal activities.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

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.     

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 of biphenyl derivatives as ACE and α-amylase inhibitors

Angiotensin converting enzyme (ACE) and α-amylase inhibitors were synthesized using 4′-(bromomethyl)-biphenyl-2-carbonitrile 1 and various cyclic secondary amines (a–h). The nitrile group appended to biphenyl was converted into tetrazole 3a–3h and the tetrazole was ring transformed into 1,3,4-oxadiazole derivatives 4a–4h. Some of the compounds have exhibited significant ACE and α-amylase inhibition.     

Synthesis and antibacterial evaluation of 3,3′-diindolylmethane derivatives

Various 3,3′-diindolylmethane (DIM) derivatives were synthesized and the antibacterial activity of these compounds were tested against ten bacterial strains and their minimum inhibitory concentration (MIC) values were determined. The MIC values of derivatives 3a–d and 5a–e were ranging from 125 to 500 μg/mL. Among these derivatives, 2-(di(1H-indol-3-yl)methyl)phenol (5a) and 3-((1H-indol-3-yl)(pyridin-3-yl)methyl)-1H-indole (5d) exhibited potent activity, showing MIC values 6.5–62.5 μg/mL against Gram positive and Gram negative bacteria. Hemolytic assay of these active DIM derivatives did not show considerable toxic effect on the normal human erythrocytes.     

A new isoflavone from Blepharis ciliaris of an Egyptian origin

A phytochemical study of the aerial parts of Blepharis ciliaris (L.) B.L. Burtt. led to the isolation of one new isoflavone glycoside caffeic acid ester: genistein-7-O-(6″-O-E-caffeoyl-β-d-glucopyranoside) (4), along with seven known compounds: methyl veratrate (1), methyl vanillate (2), protocatechuic acid (3), naringenin-7-O-(3″-acetyl-6″-E-p-coumaroyl-β-d-glucopyranoside) (5), naringenin-7-O-(6″-E-p-coumaroyl-β-d-glucopyranoside) (6), apigenin-7-O-(6″-E-p-coumaroyl-β-d-glucopyranoside) (7), and acteoside (8). Their structures were established on the basis of detailed analyses of physical, chemical, and spectral data. Compounds 1, 2, 3, 6, and 8 were isolated for the first time from this plant. The antioxidant activity of the different extracts as well as for some of the isolated compounds was evaluated.     

Synthesis and antimicrobial screening of 4-thiazolidinone and 2-azetidinone derivatives of piperazine

The Schiff’s bases 3a–3h were synthesized by reacting substituted/unsubstituted aromatic aldehydes 2a–2h with 1-(2-aminoethyl)-piperazine 1. A series of novel aryl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one 4a–4h and 3-chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-arylazetidin-2-one 5a–5h were synthesized from the Schiff’s bases of 1-(2-aminoethyl)-piperazine 3a–3h. The structures of synthesized compounds were confirmed by analytical (C, H, and N) and spectral (FT-IR, ¹H NMR, ¹³C NMR, and Mass) data. The compounds 4a–4h and 5a–5h were screened for antimicrobial activity. The compounds 4a, 4d, 4f, 4g, 5a, 5d, 5f, and 5g exhibited substantially significant antibacterial as well as antifungal activity.     

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.     

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.     

Naphthoquinones from Catalpa ovata and their inhibitory effects on the production of nitric oxide

Bioassay-guided fractionation of a CH2Cl2-soluble fraction of the stems of Catalpa ovata led to isolation of a new naphthoquinone, 4-hydroxy-2-(2-methoxy-3-hydroxy-3-methyl-but-1-enyl)-4-hydro-1H-naphthalen-1-one (10), together with nine known compounds, catalponol (1), catalponone (2), catalpalactone (3), α-lapachone (4), 9-hydroxy-α-lapachone (5), 4,9-dihydroxy-α-lapachone (6), 9-methoxy-α-lapachone (7), 4-oxo-α-lapachone (8), and 9-methoxy-4-oxo-α-lapachone (9). The structures were elucidated on the basis of spectroscopic analyses. The inhibitory effects of these isolates on lipopolysaccharide-induced NO synthesis in RAW 264.7 cells were evaluated. Among them, catapalactone (3), 9-hydroxy-α-lapachone (5) and 4,9-dihydroxy-α-lapachone (6) exhibited potent inhibitory effects, with IC₅₀ values of 9.80, 4.64 and 2.73 μM, respectively.     

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).     

Synthesis and anticonvulsant activity of novel quinazolin-4(3H)-one derived pyrazole analogs

Eighteen novel 6,8-(dibromo/unsubstituted)-2-(methyl/phenyl)-3-(4-(5-(substitutedphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)phenyl)-quinazolin-4(3H)-ones 4a–4r were designed and synthesized in good yield. Antiepileptic screening of the title compounds was performed using MES and scPTZ seizures tests while the neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 4d, 4e, 4p, 4q, and 4r were found active in MES model, while 4a, 4d, 4f, 4m, and 4p showed significant antiepileptic activity in scPTZ model. Further, all these eight compounds were administered to rats and compounds 4e, 4p, and 4q showed better activity than Phenytoin in oral route. Among these compounds 4p revealed protection in MES after i.p. administration at a dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h). The compound 4p also provided protection in the scPTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h).     

An efficient, solvent-free microwave-assisted synthesis and antimicrobial screening of 1,6-dihydropyrimidine analogues

A series of compounds 4-(4-(4-aminophenyl)-6-(aryl)-1,6-dihydropyrimidin-2-ylthio)butanenitriles 5a–l were synthesised by the reaction of allyl cyanide 4 with 3a–l. Compounds 3a–l were prepared from reaction between various chalcones 1a–l and thiourea in presence of catalytic amount of potassium hydroxide. Compounds 3a–l, and 5a–l were prepared by classical as well as MWI methods. Structures of the compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data. The newly synthesized compounds 5a–l were screened for their antimicrobial activity against different strains of bacteria and fungi using serial broth dilution method. Compounds 5e, 5g and 5k were found to be most active with MIC of 25?μg/mL against selected bacterial strains, while compound 5d, 5f, 5j and 5k were found to be most active with MIC 50?μg/mL against selected fungal strains.     

Two new steroidal saponins from the tubers ofLiriope spicata

Two novel steroidal saponins designated as spicatosidesA(1) andB(2) were isolated from the tubers ofLiriope spicata and their structures were clucidated as 25(S)-ruscogenin-1-O-β-D-glucopyranosyl (1→2)-[β-D-xylopyranosyl (1→3)]-β-D-fucopyranoside (1) and 26-O-β-D-glucopyranosyl 25(S)-22-O-methyl-furost-5-en-1β, 3β, 26-triol 1-O-β-D-glucopyranosyl (1→2)-[β-D-xylopyranosyl (1→3)]-β-D-fucopyranoside (2), respectively.     

Synthesis and antimicrobial activity of 5-chloroindoline-2,3-dione derivatives

A series of 3-(5-chloro-2-oxoindolin-3-ylideneamino)-2-arylthiazolidin-4-ones 4a–k and 5-chloro-3-(3-chloro-2-oxo-4-arylazetidin-1-ylimino)indolin-2-ones 5a–k was synthesized. The structures of final compounds were confirmed by analytical (C, H, N) and spectral (FT-IR, ¹H NMR, ¹³C NMR and Mass) data. The synthesized compounds were screened for possible antibacterial and antifungal activity. Compounds 4c, 4f, 4g, 4h, 4i, 4j, 5c, 5f, 5g, 5h, 5i and 5j showed substantially significant activity.     

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.