Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>]azepine derivatives

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.     

Conventional and microwave-assisted synthesis of imidazole and guanidine derivatives and their biological evaluation

A number of imidazole derivatives 3a–f and 4a–f have been synthesized by the condensation of 3-methylthiophen-2-carboxaldehyde 1a, 5-methylthiophen-2-carboxaldehyde 1b, N-methylpyrrol-2-carboxaldehyde 1c, 1-naphthaldehyde 1d, 2-naphthaldehyde 1e, and 2-hydroxy-1-naphthaldehyde 1f with 1,2-diaminoanthraquinone 2a and 2,3-diaminophenazine 2b, respectively. Condensation of 2-guanidinobenzimidazole with functionalized aldehydes 1a–f leads to the formation of guanidine derivatives 5a–f. Both imidazole (3a–f, 4a–f) and guanidine derivatives (5a–f) were synthesized in good yields using conventional heating and microwave irradiation techniques. Structures assigned to compounds 3a–f, 4a–f and 5a–f are supported by correct spectral and analytic data. On screening for anti-inflammatory and anticancer activities, compounds 3e, 4a and 5a exhibited good anti-inflammatory and compounds 3d, 3f, 4d and 4f showed very good anticancer activity.     

Synthesis of pyrimidine and condensed pyrimidine derivatives and their evaluation for anti-inflammatory activity

Condensation of various amines (Ia–c) with 4-isothiocyanato-4-methyl-2-pentanone (2a) at room temperature gave tetrahydropyrimidinethiones (3a–c) whereas condensation of 1a–e with 3-isothiocyanatobutanal at room temperature gave tetrahydropyrimidinethiones (4a–e). Amines 1a, d, f–i on condensation with 4-isothiocyanato-4-methyl-2-pentanone (2a) by heating under reflux for 8 h at pH ~4 (for 1a, d) and at RT (for 1f–i) gave dihydropyrimidinethiones 5a–b and 5c–f, respectively. Condensation of 1f with 3-isothiocyanatobutanal gave dihydropyimidinethione 6. When isothiocyanate (2a) and phenylenediamine derivatives 1g, h were heated under reflux at pH ~4, tricyclic compounds 7a, b were obtained in good yields. Condensation of 3-isothiocyanatobutanal with o-phenylenediamines 1h and 1j at pH ~ 5 by refluxing in methanol for 8 h gave products 8 and 9. All these compounds were screened for anti-inflammatory activity. Compounds 3c, 4c and 7a exhibited anti-inflammatory activity comparable to standard drug ibuprofen.     

Biological evaluation of novel 1,4-dithiine derivatives as potential antimicrobial agents

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.     

An efficient one-pot cyclization of quinoline thiosemicarbazones to quinolines derivatized with 1,3,4-thiadiazole as anticancer and anti-tubercular agents

A series of 6,7,8-substituted thiosemicarbazones (2a–j) of 2-chloro-3-formyl-quinoline derivatives were cyclized to the title compounds (3a–j) using acetic anhydride. The structures of the final compounds (3a–j) were confirmed by elemental and spectral (IR, ¹H NMR and MS) analysis. Some of the title compounds have shown promising anticancer and antitubercular activities.     

Iodine (III)-mediated synthesis of some 2-aryl/hetarylbenzoxazoles as antibacterial/antifungal agents

Ten 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were synthesized via oxidative cyclization of Schiff bases (3a, 3b, and 4a–h) with 1.1 equivalent of iodobenzene diacetate (IBD) in methanol. All of these 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were tested in vitro for their antibacterial and antifungal activities against Bacillus subtilis, Bacillus stearothermophilus, Escherichia coli, and Pseudomonas putida. These compounds also were screened for their antifungal activity against Aspergillus flavus and Aspergillus niger. Biological activity of these compounds was compared with those of commercially available antibiotics, chloramphenicol and antifungal agent cycloheximide. Most of these compounds, 5a, 5b, 6a, 6b, 6d, 6e, 6g, 6h, were equipotent or more potent than these commercial drugs at concentration 100 μg/ml.     

Synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives with antioxidant activity

A series of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives (2a–k) bearing different amino acids were synthesized by base condensation reaction. 3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one(2) was obtained by N-acylation of 5H-dibenz[b,f]azepine (1). All the synthesized compounds were evaluated for their potential over antioxidant activities against inhibition of lipid peroxidation by β-carotene and linoleic acid assay and inhibition of human low-density lipoprotein (LDL) oxidation assay. Typically, compound 2 showed weak antioxidant activity, whereas coupling of different amino acids enhances the antioxidant activities based on the presence of different functional groups. Among the derivatives, compound 2d showed significant antioxidant activities followed by 2h, 2i, 2j and 2k.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

EGFR tyrosine kinase targeted compounds: synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives

The preparation of new quinazoline and benzo[d]isothiazole-based antitumor agents is described. The target compounds fall into three groups including the N-substituted derivatives 2a–d, the substituted amino derivatives 4–6a–d, and the dimeric compounds 7–9a,b. Docking study of the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. All compounds were tested, in vitro, for their activity against human mammary carcinoma cell line (MCF7) in which EGFR is highly expressed. All compounds showed significant growth inhibitory activity. The remarkable activity of the bis quinazoline derivative 8a (IC₅₀ = 0.06 μg/ml; 1.64 nmol/ml) is to be noted.     

Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity

A novel series of 1,3-diarylpyrazole derivatives (4–8), analogues to lonazolac, were designed, synthesized, and evaluated for their anti-inflammatory as well as analgesic activities. To target preferential cyclooxygenase-2 (COX-2) inhibitors, the design of these compounds was based upon two different molecular modeling studies. The first study included fit-comparison study of conformational models of compounds 4–8 with a novel validated COX-2 inhibitors hypothesis generated from the corresponding leads I–V using Hip-Hop CATALYST software. The second study included docking study of the designed compounds 4–8 with binding site of COX-1 and COX-2 enzymes using internal coordinate mechanics (ICM)-Pro software. The reported Akaho method was then used to predict the COX-2 preferentiality of the designed compounds. The designed molecules were synthesized and screened for in vivo anti-inflammatory and analgesic activity. Compounds 4a, 6a, and 8b showed high activity in comparison with indomethacin, consistent with virtual molecular modeling studies.     

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

The synthesis of new indole derivatives bearing isoxazoline moiety (3a–d and 4a–d) has been described. IR, ¹H NMR, and mass spectral data supported the structures of synthesized compounds. The compounds were tested in vivo for their anti-inflammatory activity by carrageenin-induced rat paw edema method. The compounds that showed good anti-inflammatory activity were screened for their ulcerogenic and lipid peroxidation activities. The most active compound of this series is 3-[3-(4-methoxyphenyl)- 4-morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-5yl]-1H-indole 4d.     

Design and synthesis of novel piperazine unit condensed 2,6-diarylpiperidin-4-one derivatives as antituberculosis and antimicrobial agents

Abstract  

A new series of 1-[2-(4-ethoxycarbonylpiperazine-1-yl)acetyl]-2,6-diarylpiperidin-4-ones (3a–3j) has been synthesized by conventional method and were characterized by IR, elemental analysis, mass spectral, ¹H NMR, ¹³C NMR, and single crystal X-ray diffraction analysis. The synthesized compounds were evaluated for their antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC-27294) and also its antimicrobial activity were examined against five familiar bacterial and fungal strains. Among the synthesized compounds, compounds 3e–3j exhibit higher inhibition potency (16 μg/ml) against M. tuberculosis H37Rv. Furthermore, compounds containing fluoro substituent in the phenyl ring at C-2 and C-6 positions of the piperidin-4-one motif (compounds 3c, 3d, and 3i) exerted better antibacterial and antifungal activity than the other phenyl-substituted compounds.     

Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study

A series of novel gabapentin derivatives 6a–k and 7a–f were synthesized, and their biological activities were determined. The chemical structures were confirmed by elemental analyses, UV–visible, FT-IR, and ¹H NMR spectral studies. The structure–activity relationships (SAR) for anticonvulsant and antioxidant activities were discussed. Compounds 7a–f were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test, and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 7b and 7e showed good protective effect from seizure when compared to standard drug, phenytoin (100 mg/kg). The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). Most of the novel compounds showed DPPH radical scavenging activity, where compounds 6f, 6j, and 7a were the best radical scavengers (IC₅₀ was about 60 μg/ml).     

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 of benzo[b][1,4]oxazin-3(4H)-ones via smiles rearrangement for antimicrobial activity

The benzo[b][1,4]oxazin-3(4H)-one derivatives, 1a–p, carrying F, Br, and Cl on the benzene ring, or benzyl, cyclohexyl, n-hexyl, and tetrafuryl methylene groups attached to nitrogen atom were synthesized via Smiles rearrangement and assayed in vitro for their antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. The antimicrobial activity of the benzo[b][1,4]oxazin-3(4H)-ones showed, on the whole, potency toward all the tested Gram-positive and Gram-negative microorganism (MIC ranging from 16 to 64 μg/ml), whereas weak effectiveness was exhibited against fungi. Data obtained suggest that fluorine atom in the compounds, 1c, 1f, 1i plays an important role in enhancing the antimicrobial properties of this class of compounds. These observations provide some predictions to design further antimicrobial active compounds prior to their synthesis according to molecular modeling studies.     

A facile synthesis of some 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones and their biological evaluation as anticancer agents

The synthesis of some new 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones supported with various pharmacophores and functionalities at positin-1 is described. The in vitro anticancer activity of 24 of the newly synthesized compounds was evaluated according to the protocol of the NCI in vitro disease-oriented human cells screening panel assay. The results revealed that five compounds 4a–c, 7b, and 12b were able to display moderate antitumor potential against some of the tested subpanel tumor cell lines at the GI₅₀ and TGI levels, however, with marginal or no cytotoxic (LC₅₀) activity. The obtained data suggested that better antitumor activity was linked to derivatives with either 4-bromophenyl or 3,4-dimethoxyphenyl moieties, together with a 1-methyl-1H-pyrrol-2-yl counter part at positions 6 and 4, respectively. Consequently, the 3-cyano-4-(1-methyl-1H-pyrrol-2-yl)-6-(4-bromophenyl or 3,4-dimethoxyphenyl)-2(1H)-pyridinones 4a and 4b, could be considered as the most active members identified in this investigation as evidenced from their relative higher growth inhibitory (GI₅₀ (MG-MID) 77.6 and 67.6 μM, respectively) and cytostatic (TGI (MG-MID) 85.1 and 95.5 μM, respectively) activities, when compared with the substituted thiocarbamoyl analog 7b and the bicyclic [1,2,4]triazolo[3,4-a]pyridine derivative 12b.     

Design, synthesis and preliminary evaluation of some novel [1,4]diazepino [5,6-b]pyrrolizine and 6-(2-oxopyrrolidino)-1H-pyrrolizine derivatives as anticonvulsant agents

New series of diazepino[5,6-b]pyrrolizines 7a–c and 8a–c and 6-(2-oxopyrrolidino)-1H-pyrrolizines 10a–c were synthesized through acylation of the key aminonitrile derivatives 5a–c (Scheme 1) with the appropriate acid chlorides. Subsequent cyclization reaction yielded the target compounds (Schemes 2, 3). The chemical structure of the synthesized compounds was elucidated by spectral and elemental analyses. The synthesized compounds were evaluated for their ability to protect mice against PTZ-induced seizures, the most active compounds were 10a–c where compound 10b exhibited 67.9% relative potency compared to phenobarbitone and compound 10a provided the maximum protection % of all compounds (60%) at dose of 50 mg/kg comparable to phenobarbitone at a dose of 20 mg/kg.     

3,5-Disubstituted thiadiazine-2-thiones: New cell-cycle inhibitors

Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a–9a and 3b, 4b, 6b–9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC₅₀ = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.     

Synthesis,in vitro cytotoxicity,and anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes

Synthesis and evaluation of cytotoxicity and anti-microbial activity of a series of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butane derivatives comprising thioether functionality and other pharmacophore modifications are described. All the newly synthesized compounds were characterized by IR, NMR, elemental analyses, and mass spectral studies. The compounds 4a–f, 5a–f, and 6a–f were evaluated for in vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29, and Breast Cancer MDA MB-231. All the compounds were subjected to in vitro anti-bacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC-27853) and their minimal inhibitory concentrations were determined.     

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N′-aryl methylidene acetohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8). 1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.