In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

BACKGROUND: The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action. METHODS: The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site. RESULT: Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively. CONCLUSION: Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

Importance of Pharmacophore in Designing Anticonvulsant Agents.

Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity with structural diversity and common pharmacophoric features. For the first time (1995), Dimmock and his team introduced specific arrangements of three important pharmacophores for anticonvulsant activity. These pharmacophores include two hydrophobic binding sites and one hydrogen binding site. After a few years (2012), Pandeya modified Dimmock's concept by adding one more pharmacophoric feature as an electron donor in the previously suggested pharmacophoric arrangement of the anticonvulsant. As a result, numerous scientists designed anticonvulsant drugs based on Dimmock's and Pandeya's concept. In addition, marketed anticonvulsant preparation containing Riluzole, Phenobarbital, Progabide, Ralitoline, etc., also holds the suggested pharmacophores by Dimmock and Pandeya's pharmacophoric concept. This review mainly focuses on the compilation of reported scientific literature in the last decade on the pharmacophoric features of different heterocyclic anticonvulsants, which will help develop new anticonvulsants.

Recent Development in Substituted Benzothiazole as an Anticonvulsant Agent.

Heterocyclic compounds and their derivatives gained more attention due to their valuable biological and pharmacological properties. Benzothiazole is a heterocyclic structure containing a bicyclic ring system with a large panel of applications. The benzothiazole is present in many new products undergoing research hoping that it possesses various biological activities. Epilepsy is a diverse group of diseases marked by neuronal excitability and hypersynchronous neuronal activity of motor, sensory or autonomic events with or without loss of consciousness. Presently, many antiepileptic drugs like lamotrigine, stiripentol tiagabine, pregabalin, felbamate, and topiramate are available and effective towards 60-80% of patients only, along with undesirable side effects, such as hepatotoxicity, gastrointestinal disturbance, drowsiness, gingival hyperplasia, and hirsutism. Thus, many attempts are still on-going to develop antiepileptic drugs with a safer profile. This review is mainly focused on the compilation of reported scientific literature data in the recent one-decade on the anticonvulsant activity of benzothiazole compounds.

Reversed-phase liquid chromatography with electrospray mass detection and 1H and 13C NMR characterization of new process-related impurities, including forced degradants of efavirenz: related substances correlated to the synthetic pathway.

In this study, a stability-indicating reversed-phase liquid chromatographic electrospray mass spectrometric method was developed and validated for the determination of process-related impurities and forced degradants of Efavirenz in bulk drugs. Efavirenz was subjected to acid, alkaline hydrolysis, H2O2 oxidation, photolysis, and thermal stress. Significant degradation was observed during alkaline hydrolysis, and the degradants were isolated on a mass-based purification system and characterized by high-resolution mass spectrometry, positive electrospray ionization tandem mass spectrometry, and (1)H and (13)C NMR spectroscopy. Accurate mass measurement and NMR spectroscopy revealed the possible structure of process-related impurities and degradant under stress conditions. The acceptable separation was accomplished on Waters bondapak C18 column (250 mm × 4.6 mm; 5 µm), using 5 mM ammonium acetate and acetonitrile as a mobile phase in a gradient elution mode at a flow rate of 1.0 mL/min. The eluents were monitored by diode array detector at 247 nm and quantitation limits were obtained in the range of 0.1-2.5 µg/mL for Efavirenz, degradants, and process-related impurities. The liquid chromatography method was validated with respect to accuracy, precision, linearity, robustness, and limits of detection and quantification as per International Conference on Harmonization guidelines.

Stability-indicating RP-HPLC method for the simultaneous determination of escitalopram oxalate and clonazepam.

The objective of the current study was to develop a validated, specific stability-indicating reversed-phase liquid chromatographic (LC) method for the quantitative determination of escitalopram oxalate and clonazepam and their related substances in bulk drugs and pharmaceutical dosage forms in the presence of degradation products. Forced degradation studies were performed on the pure drugs of escitalopram oxalate and clonazepam, as per the stress conditions prescribed by the International Conference on Harmonization (ICH) using acid, base, oxidation, thermal stress and photolytic degradation to show the stability-indicating power of the method. Significant degradation was observed during acid and alkaline hydrolysis and no degradation was observed in other stress conditions. The chromatographic method was optimized using the samples generated from forced degradation studies. Good resolution between the peaks corresponded to the active pharmaceutical ingredients, escitalopram oxalate and clonazepam, and degradation products from the analyte were achieved on an ODS Hypersil C18 column (250 × 4.6 mm) using a mobile phase consisting of a mixture of acetonitrile-50 mM phosphate buffer + 10 mM triethylamine (70:30, v/v). The detection was conducted at 268 nm. The limit of detection and the limit of quantitation for escitalopram oxalate and clonazepam were established. The stress test solutions were assayed against the qualified working standards of escitalopram oxalate and clonazepam, which indicated that the developed LC method was stability-indicating. Validation of the developed LC method was conducted as per ICH requirements. The developed LC method was found to be suitable to check the quality of bulk samples of escitalopram oxalate and clonazepam.

Study on sustained-release metformin hydrochloride from matrix tablet: Influence of hydrophilic polymers and in vitro evaluation.

The overall objective of the present work was to develop an oral sustained-release (SR) metformin tablet prepared by the direct compression method, using hydrophilic hydroxylpropylmethylcellulose (HPMC) and Guar gum polymer alone and in combination at different concentrations. Metformin hydrochloride (HCl), a biguanide, has a relatively short plasma half-life and low absolute bioavailability. All the batches were evaluated for thickness, weight variation, hardness and drug content uniformity and in vitro drug release. Mean dissolution time is used to characterize the drug release rate from a dosage form, and indicates the drug release-retarding efficiency of the polymer. The hydrophilic matrix of HPMC alone could not control the Metformin release effectively for 12 h whereas when combined with Guar gum, it could slow down the release of drug and, thus, can be successfully employed for formulating SR matrix tablets. Fitting the data to the Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. Similarity factor ƒ2 values suggest that the test and reference profiles are identical.