Aida A. El-Azzouny

Synthesis and Anti‐Candida Potential of Certain Novel 1‐[(3‐Substituted‐3‐phenyl)propyl]‐1H‐imidazoles

The synthesis and anti‐Candida activity of 1‐[(3‐aroyloxy‐3‐phenyl)propyl]‐1H‐imidazoles 5a–f and 1‐[(3‐alkyl/aralkyl/phenyl‐3‐phenyl)propan‐3‐ol]‐1H‐imidazoles 5g–j are reported. The influence of the ester formation and different substitutions on the anti‐Candida activity of the alcohol 4 was investigated. Among the newly developed bioactive chemical entities, compounds 5b and 5c displayed minimum inhibitory concentrations (MICs) against Candida albicans and Candida pseudotropicales comparable to that of tioconazole and more potent than miconazole.

Design, synthesis and antibacterial potential of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-1-substituted-4,5-dihydropyrazoles.

A series of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-1-substituted-4,5-dihydropyrazole derivatives 4a–e and 6a–g have been synthesized and spectrally characterized. The antibacterial activity of the novel candidates has been screened using the agar diffusion test. These compounds were endowed with high antibacterial activity against different Gram +ve and Gram −ve bacteria when compared with standard antibacterial drugs. In the light of zone of inhibition and MIC results, Sarcina and Staphylococcus aureus are the most sensitive bacteria where pyrrolidinomethanone derivative 4e showed MICs at 80 and 110 nM, respectively. While hydroxypiperidinoethanone derivative 6c showed MIC at 90 nM for Sarcina.

Anticonvulsant potential of certain new (2E)-2-[1-Aryl-3-(1H-imidazol-1-yl)propylidene]-N-(aryl/H)hydrazinecarboxamides.

Anticonvulsant potential and neurotoxicity of certain new imidazole-containing arylsemicarbazones 6a–p are reported. The test compounds 6a–p exhibited anticonvulsant activity mainly in the scPTZ screen. Compound 6p emerged as the most active surrogate displaying 100% protection at a dose level of 636 μmol/kg in the scPTZ screen without any neurotoxicity. The assigned (E)-configuration of the title compounds 6a–p was confirmed via single crystal X-ray structure of compound 6g.

A Validated HPLC Method for Separation and Determination of Promethazine Enantiomers in Pharmaceutical Formulations

A simple, rapid, and validated method for separation and determination of promethazine enantiomers was developed. Promethazine was separated and quantitated on a Vancomycin Chirobiotic V column (250 × 4.6 mm), using a mixture of methanol, acetic acid, and triethylamine (100:0.1:0.1%, by volume) as a mobile phase at 20°C and at a flow rate of 1 mL/min. The UV-detector was set to 254 nm. Acetyl salicylic acid (Aspirin®) was used as an internal standard. The applied HPLC method allowed separation and quantification of promethazine enantiomers with good linearity (r > .999) in the studied range. The relative standard deviations (RSD) were 0.29 and 0.36 for the promethazine enantiomers with accuracy of 100.06 and 100.08. The limit of detection and limit of quantification of promethazine enantiomers were found to be 0.04 and 0.07 μg/mL, respectively. The method was validated through the parameters of linearity, accuracy, precision, and robustness. The HPLC method was applied for the quantitative determination of promethazine in pharmaceutical formulations.

Riluzole: Validation of Stability-Indicating HPLC, D1 and DD1 Spectrophotometric Assays

A stability-indicating reversed-phase high-performance liquid chromatographic assay procedure has been developed and validated for riluzole in the presence of alkaline and oxidative degradation products. The liquid chromatographic separation was achieved and compared isocratically on C18 Zorbax ODS and Poroshell 120 EC-C18 columns by using a mobile phase containing methanol-water, pH = 3.10 (70:30, v/v), at a flow rate of 1 mL/min and ultraviolet detection at 264 nm. The method was linear over the concentration ranges of 20-200 µg/mL (r = 0.9997) and 10-200 µg/mL (r = 0.9995). The limit of detection and quantitation for the two columns were 2 and 6 µg/mL and 1 and 3 µg/mL, respectively. Moreover, spectrophotometric methods were applied for the determination of riluzole in the presence of its oxidative degradation products by using first derivative spectrophotometry at 252.5 and 275.0 nm. The method was linear over the concentration range of 1-20 µg/mL (r = 0.9995 and 0.9996) at the studied wavelengths, with limits of detection and quantitation of 0.1 and 0.3 µg/mL. In addition, the first derivative ratio spectrophotometry (DD1) method was applied for the determination of riluzole in the presence of its alkaline degradation product at 252.0, 278.5 and 306.3 nm by using 100 µg/mL of alkaline degraded riluzole as a divisor; riluzole was additionally determined in the presence of its hydrogen peroxide oxidative degradation products at 252.5, 275.0 and 305.0 nm by using 200 µg/mL of oxidative degraded riluzole as a divisor. The DD1 method was linear over the concentration range of 1-20 µg/mL (r = 0.9996, 0.9995 and 0.9996 for the alkaline degradation product at the three studied wavelengths, respectively; and r = 0.9995, 0.9996 and 0.9995 for the oxidative degradation product at the three studied wavelengths, respectively), with limits of detection and quantitation of 0.1 and 0.3 µg/mL for both alkaline and oxidative degradation products. The two studied chromatographic and spectrophotometric methods were comparable and display the required accuracy, selectivity, sensitivity and precision to assay riluzole in bulk and pharmaceutical dosage forms. Degradation products resulting from the stress studies did not interfere with the detection of riluzole, which indicates that these are stability-indicating assays.

Validated HPLC Method for Separation and Determination of Terbutaline Enantiomers

Abstract A simple, rapid, and validated method for separation and determination of terbutaline enantiomers was developed. Terbutaline was separated and determined on a Vancomycin Chirobiotic V column (250 × 4.6 mm), using a mixture of methanol, acetic acid, and triethylamine (100:0.1:0.1% v/v/v) as a mobile phase at 20°C and at a flow rate of 1 ml/min. The UV detector was set to 276 nm. Acetyl salicylic acid (aspirin) was used as an internal standard. The applied high-performance liquid chromatography (HPLC) method allowed separation and quantification of terbutaline enantiomers with good linearity (r > 0.999) in the studied range. The relative standard deviations (RSD) were 1.10 and 1.32% for the terbutaline enantiomers with accuracy of 99.80 and 99.55. The limit of detection and limit of quantification of terbutaline enantiomers were found to be 0.05 and 0.10 µg · ml−1, respectively. The method was validated through the parameters of linearity, accuracy, precision, and robustness. The HPLC method was applied for the quantitative determination of terbutaline in pharmaceutical formulations.

Anticonvulsant Profiles of Certain New 6-Aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-Aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a–l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones (6m–x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino]cycloalkanecarboxamides (3a–f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a–f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a–f which were cyclized under mild conditions to give the spiro compounds 5a–f. Ultimately, compounds 5a–f were alkylated or aralkylated to give the target compounds 6a–i and 6m–u. On the other hand, compounds 6j–l and 6v–x were synthesized from the intermediates 5a–f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a–x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a–x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.

Design and synthesis of certain substituted cycloalkanecarboxamides structurally related to safinamide with anticonvulsant potential

A series of novel safinamide derivatives were synthesized and biologically evaluated for their anticonvulsant activity against maximal electroshock seizure assay and subcutaneous pentylenetetrazole (s.c. PTZ) screening test. Compound 13b is the most active derivative in s.c. PTZ screening test with an ED50 value lower than that of safinamide by about tenfold. A molecular modeling study, including fitting to sodium channel blockers 3D-pharmacophore model and docking into a branched-chain aminotransferase enzyme active site were consistent with the in vivo results.

Synthesis of certain N-aralkyl-N-(1-((cyclohexylamino)methyl)cyclohexyl)benzenamines and benzamides and their anticonvulsant and analgesic potential

Background and objectives Epilepsy is a central nervous system disorder, affecting about 1% of the world′s population, and is mostly prevalent in developing nations. In addition, many geminally disubstituted cyclohexane derivatives have proven to have anticonvulsant and analgesic activities. The aim of this study was to synthesize a new series of N-aralkyl-N-(1-((cyclohexylamino)methyl)cyclohexyl)benzenamines, 6a-h, and N-(1-((cyclohexylamino)methyl)cyclohexyl)-N-phenyl-substituted benzamides, 8a-g, for the purpose of evaluating their anticonvulsant and analgesic potential. In addition, the in-silico properties of the newly synthesized compounds have been discussed. Materials and methods Starting from 1-(N-phenylbenzamido and 4-substituted benzamido)cyclohexane carboxylic acids 3a-g, a new series of N-aralkyl-N-(1-((cyclohexylamino)methyl)cyclohexyl)benzenamines, 6a-h, was synthesized through formation of the corresponding methyl esters 4a-g, which underwent complete reduction of both the ester and the tertiary amidic carbonyl groups to afford the desired amino alcohols, 5a-g. Condensation of the corresponding mesylate esters with cyclohexylamine gave the target diamines 6a-g. Also, the alcohols 7a-g were achieved from 3a-g using NaBH 4 without affecting the amidic group, followed by preparation of the corresponding intermediate mesylate esters, which reacted with cyclohexylamine to yield the benzamidecyclohexyl amines 8a-g. The anticonvulsant and analgesic properties of 6a-h and 8a-h were studied using the pentylenetetrazole screening test and the hot-plate technique, respectively. Results and conclusion The results of the present study revealed that the most active compounds that exhibited remarkable 100% protection in mice were 6b , 6d , 6e , 8a, 8b , 8f and 8h, compared with diphenylhydantoin sodium and valproic acid, which were used as reference drugs. Both N-aralkyl-N-(1-((cyclohexyl amino)methyl)cyclohexyl)benzenamine and N-(1-((cyclohexylamino)methyl)cyclohexyl)-N-phenyl-substituted benzamide series, 6a-h and 8a-h, displayed significant antinociceptive effects. However, the 6a-h series showed higher potential than the 8a-h one. The results of the in-silico studies for the newly synthesized compounds showed that compounds 6c , 6e , 6h , 8e , 8f and 8h exhibit low mutagenic, tumorigenic, reproductive and medium irritant effect, as well as good drug-likeness and drug score.

Synthesis and Single Crystal X-Ray Structure of New (2E)-2-[3-(1H-Imidazol-1-yl)-1-phenylpropylidene]-N-phenylhydrazinecarboxamide

Synthesis, spectroscopic characterization and X-ray crystal structure of a new (2E)-2-[3-(1H-imidazol-1-yl)-1-phenylpropylidene]-N-phenylhydrazinecarboxamide (4) are reported. The stereochemistry of the title compound 4, C19H19N5O, about the imine bond [1.296 (4) A] was assigned to have (E)-configuration. In the urea moiety, the N–H entities are trans to each other, and one of these forms is an intramolecular N–H⋯H hydrogen bond. The compound crystallizes in the monoclinic space group P21/c with a = 5.8093 (2) A, b = 20.5575 (6) A, c = 14.0355 (5) A, α = 90.00°, β = 97.365° (2), γ = 90.00°, V = 1662.36 (10) A3, and Z = 4. The molecules are packed in crystal structure by weak intermolecular hydrogen interactions.