Rajashri R. Naik

Molecular Modeling, Synthesis and Pharmacological Evaluation of 1,3,4- Thiadiazoles as Anti-inflammatory and Analgesic Agents

A series of novel substituted 2-amino-5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazoles were designed, synthesized and evaluated as anti-inflammatory and analgesic agents. Compounds were characterized by elemental and spectroscopic analysis. Compounds possessing significant activities were screened for ulcerogenic activity. Compound-5 (2-(4-isobutylphenyl)-N-(5-(1-(4- isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-yl)-propanamide) produces significant in vitro antiinflammatory activity (72.5%) as compared to ibuprofen (47.7%), while compound-3f (2-(Ncyclohexyl- N-methylamino)-N-(5-(1-(4-isobutylphenyl)-ethyl)-1,3,4-thiadiazol-2-yl)-acetamide) showed 64.1% activity. Results indicate that compound-4 (N-(5-(1-(4-isobutyl-phenyl)-ethyl)-1,3,4-thiadiazol-2-yl)-acetamide) exhibited highest analgesic activity (69.8%), where as compound-5 possessed 65.5% activity. Structure based drug design was also investigated to reveal the mechanism of action and specificity of our compounds against COX-2 enzyme. Anti-inflammatory activity and ulcerogenic potential were in agreement with the molecular modeling studies carried out on cycloxygenase enzyme.

Fatty Acids Analysis, Antioxidant and Biological Activity of Fixed Oil of Annona muricata L. Seeds

The total oil yield and the fatty acid composition were determined in the Annona muricata L. fixed oil using organic solvent extraction and GC-FID. The seeds were found to contain about ~21.5% of crude fixed oil on a dry weight basis. The crude oil containing fatty acid was converted into methyl esters and analysed by GC-FID. Fourteen fatty acids were identified using GC-FID. The major monounsaturated and saturated fatty acids were oleic acid (39.2%) and palmitic acid (19.1–19.2%), respectively, whereas the α-linolenic acid (1.2%) and linoleic acid (34.9%) were polyunsaturated fatty acid. The other saturated acids were stearic acid (3.3%), arachidic acid (0.4%), myristic acid (0.1%), heptadecanoic acid (0.1%), behenic acid (0.1%), and lignoceric acid (0.1%). Some of the fatty acids have not been reported earlier from the oil of Annona muricata L. Fixed oil exhibited significant free radical scavenging activity which was measured using DPPH and is also known to inhibit the gastrointestinal motility significantly.

Design, synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant agent

Abstract A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran- 3-yl)-2-(substituted)-acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl( methyl) amino)-acetamide] (5i) and [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1- yl)-acetamide] (5c) demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl)-acetamide] (5f) exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.

Stability-Indicating HPLC Determination of Gemcitabine in Pharmaceutical Formulations

A simple, sensitive, inexpensive, and rapid stability indicating high performance liquid chromatographic method has been developed for determination of gemcitabine in injectable dosage forms using theophylline as internal standard. Chromatographic separation was achieved on a Phenomenex Luna C-18 column (250 mm × 4.6 mm; 5μ) with a mobile phase consisting of 90% water and 10% acetonitrile (pH 7.00 ± 0.05). The signals of gemcitabine and theophylline were recorded at 275 nm. Calibration curves were linear in the concentration range of 0.5–50 μg/mL. The correlation coefficient was 0.999 or higher. The limit of detection and limit of quantitation were 0.1498 and 0.4541 μg/mL, respectively. The inter- and intraday precision were less than 2%. Accuracy of the method ranged from 100.2% to 100.4%. Stability studies indicate that the drug was stable to sunlight and UV light. The drug gives 6 different hydrolytic products under alkaline stress and 3 in acidic condition. Aqueous and oxidative stress conditions also degrade the drug. Degradation was higher in the alkaline condition compared to other stress conditions. The robustness of the methods was evaluated using design of experiments. Validation reveals that the proposed method is specific, accurate, precise, reliable, robust, reproducible, and suitable for the quantitative analysis.

Molecular modeling, synthesis, characterization and pharmacological evaluation of benzo[d]oxazole derivatives as non-steroidal anti-inflammatory agents

A series of N-(2-(4-chlorobenzyl)benzo[d]oxazol-5-yl)-3-substituted-propanamide (3a–3n) were synthesized and evaluated for their acute and chronic anti-inflammatory potential. The structure of the compounds was elucidated by elemental and spectral (IR, 1H NMR and MS) analysis. The synthesized compounds (at a dose of 20 mg/kg b.wt. p.o.) have shown their ability to provide 45.1–81.7% protection against carrageenan-induced paw edema, in comparison with diclofenac sodium (69.5%) and ibuprofen (64.7%). The most active compounds 3a, 3l and 3n were screened for chronic anti-inflammatory activity (cotton-pellet-induced granuloma) and to study their ulcerogenic activity. Compounds 3a, 3l and 3n showed 48.4%, 39.3% and 44.0% protection against cotton pellets-induced granuloma compared to diclofenac sodium (60.2%). The tested compounds were less ulcerogenic than the ibuprofen. Molecular modeling studies suggest that these compounds have strong interaction with the COX-2 enzyme, which is responsible for the activity.

Fatty Acids Analysis and Antioxidant Activity of Fixed Oil of Quercus Infectoria Grown in Jordan

Quercus infectoria seeds were used in the present study, and fatty acid content in fixed oil was determined using GC-FID. The total amount of the oil present in the seed was 7.2%. The major fatty acid identified were oleic acid (58.13%), linoleic acid (19.84%), palmitic acid (15.99%), stearic acid (2.27%), α–linolenic acid (1.31%) and other constituents like heptadecanoic acid, cis-11-eicosenoic acid, cis-10-heptadecenoic acid, behenic, lignoceric and myristic acid with less the 1%. Due to its phenolic compounds and α-tocopherol, the oil exhibits its antioxidant activity. Antioxidant properties of the oil were determined via DPPH radical scavenging and β-carotene bleaching assay. The physical properties and UV and FT-IR spectra were also determined. keywords: Quercus infectoria, Fixed oil, Antioxidant, GC-FID, α-tocopherol, Fatty acid methyl ester (FAME), DPPH radical scavenging activity, β-carotene bleaching assay, Oleic acid, Linoleic acid, Palmitic acid, FT-IR, UV spectrum.

First-Pass Metabolism Considerations in Pharmaceutical Product Development

Abstract The first-pass metabolism of a drug mainly in the gastrointestinal tract (GIT) and liver is considered as an almost unavoidable obstacle that can greatly reduce the systemic bioavailability as well as the efficacy of an orally administered drug. Therefore it is of prime importance during the process of drug development to gain proper insight and consider the various physicochemical or biochemical and physiological factors like molecular properties of drug, enzyme induction and inhibition, disease state, and others affecting the first-pass metabolism of a drug in order to design an appropriate formulation with proper excipients. This chapter mainly emphasizes the role of various physiological and biochemical factors affecting the first-pass metabolism of a drug in GIT and liver, such as of gastrointestinal motility, hepatic blood supply, plasma protein binding, genetic polymorphism, dose, and route of administration of drugs. The chapter is also contextualized with the role of prodrug development in order to circumvent the first-pass metabolism as well as to increase the bioavailability and efficacy of drugs.