Current Drug Discovery Technologies - Volume 15, Issue 4, 2018

Background: Asthma is defined as a heterogeneous disease usually characterized by chronic airway inflammation (GINA 2016) affecting almost 334 million people worldwide (Global asthma report 2014). Treatment of asthma with a long-acting bronchodilator is important because it reduces the symptoms that occur at night or in the early morning and it is very effective to use as a long term control medication for asthma by preventing asthmatic symptoms. The main objective of this review is to describe the impurity profile and force degradation studies for three major classes of bronchodilators namely β2-adrenoceptor agonists, muscarinic receptor antagonists and xanthine. Unidentified and potential toxic impurities are hazardous to health, so in order to increase the safety of drug therapy; impurities should be identified and determined by selective analytical methods. Methods: Different conditions for degradations like hydrolytic (acidic, basic and neutral), oxidative, photolytic and thermolytic have been discussed in detail for bronchodilators. Furthermore, it is discussed with the name along with number of impurities and degradants present in different matrices including its clinical implication. The name as well as structures of all the observed impurities in different bronchodilators is included, which can aid in impurity profiling. Various analytical methods, including Chromatographic techniques like TLC; HPTLC; HPLC; GC, Spectroscopic techniques like UV; IR; NMR; MS and hyphenated techniques like GC-MS; LC-MS; CE-MS; SFC-MS; LC-NMR; CENMR; LC-FTIR has been used for the identification and quantification of impurities. A general scheme has been presented for the impurity profiling. Result: Nineteen articles, six patents and fifteen drugs are included in this review. In that, majority (7) of papers are based on HPLC-UV, 5 papers are based on LC-MS, 2 papers are based on LC-MS-NMR, 1 paper is based on LC-NMR, 1 paper is based on GC-MSNMR, 1 paper is based on GC-UV and 1 paper is based on TLC-UV technique for isolation and characterization of impurities. In salbutamol, 7 degradants were found by LC-MS as compare to 4 degradants by HPLC-UV. In bambuterol, 12 degradants were found by LC-MS-NMR as compare to 4 degradants by LC-MS. Conclusion: After a thorough literature search, LC-MS and LC-MS-NMR techniques are found most useful for impurity profiling. In future, LC-DAD-NMR-MS, CE-ESI-FTICR- MS can also be explored for the isolation and characterization of impurities.

Background: Gastroesophageal reflux disease (GERD) is one of the most common diseases in society, affecting up to 40% of the population. It has major impact on the quality of life and a high burden on medical expenditure. In this work, herbs used by ancient Iranians to treat GERD have been introduced. Methods: Different well-known Persian textbooks and recent electronic databases were searched to explore the treatment of GERD and the pharmacological mechanisms of the identified medicinal plants. Results: GERD has been known for many centuries, and many herbal remedies for its treatment have been elucidated in traditional medical literature. We found 25 medicinal herbs in Persian medicine books and searched for evidence to support them in the current literature. Conclusion: Although their active components or the mechanism of action were not known by the ancient Persians at that time, their persistent use during different centuries might indicate their effectiveness. Owing to their potential, medicinal herbs are a viable option for the treatment of diseases like GERD even today.

Background: A series of novel sulphonylureas/guanidine derivatives was designed, synthesized, and evaluated for the treatment of diabetes mellitus. In this study, the designed compounds were docked with AKR1C1 complexes by using glide docking program and docking calculations were performed to predict the binding affinity of the designed compounds with the binding pocket of protein 4YVP and QikProp program was used to predict the ADME/T properties of the analogues. Methods: All the targeted derivatives were synthesized and purified by recrystallization. Synthesized compounds were characterized by various physicochemical and various spectroscopic techniques like melting point, thin layer chromatography, infrared spectroscopy (KBr pellets), mass spectroscopy(m/z), 1H NMR (DMSO-d6), and 13C NMR. The synthesized compounds were further studied for biological evolution by alloxan (150 mg/dl, intraperitonial) induced diabetic rat model for in-vivo studies. Result: Among all the synthesized derivatives, 5c and 5d were most potent as per binding energy. Compound 5i have shown a better plasma glucose reduction compared to glibenclamide. Hence, it will be further used as a lead compound to develop a more such kind of agent. Conclusion: The docking study revealed that in all designed sulphonylureas/ guanidine series of compounds 5c and 5d were found to be most potent compounds as per the binding energy compared to glibenclamide. With the help of detailed study of in vivo biological activity, we observed that compound 5i gives better result compared to glibenclamide as standard.

Background: Chinese tree shrews (Tupaia belangeri chinensis) bear several characteristics that are considered to be very crucial for utilizing in animal experimental models in biomedical research. Subsequent to the identification of key aspects and signaling pathways in nervous and immune systems, it is revealed that tree shrews acquire common as well as unique characteristics, and hence offer a genetic basis for employing them as a prospective model for biomedical research. CD59 glycoprotein, commonly referred to as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is encoded by the CD59 gene in human beings. It is the member of the LY6/uPAR/alpha-neurotoxin protein family. Objectives: With this initial point, the objective of this study was to determine a comparative composite based structure of CD59 of Chinese tree shrew. The additional objective of this study was to examine the distribution of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, hydrophobicity molecular surface analysis and electrostatic potential analysis with the assistance of several bioinformatical analytical tools. Methods: CD59 Amino acid sequence of Chinese tree shrew was collected from the online database system of National Centre for Biotechnology Information. SignalP 4.0 online server was employed for detection of signal peptide instance within the protein sequence of CD59. Molecular model structure of CD59 protein was generated by the Iterative Threading ASSEmbly Refinement (I-TASSER) suite. The confirmation for three-dimensional structural model was evaluated by structure validation tools. Location of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, and hydrophobicity molecular surface analysis was performed with the help of Chimera tool. Electrostatic potential analysis was carried out with the adaptive Poisson-Boltzmann solver package. Subsequently validated model was used for the functionally critical amino acids and active site prediction. The functionally critical amino acids and ligand- binding site (LBS) of the proteins (modeled) were determined using the COACH program. Result: Analysis of Ramachandran plot for Chinese tree shrew depicted that overall, 100% of the residues in homology model were observed in allowed and favored regions, sequentially leading to the validation of the standard of generated protein structural model. In case of CD59 of Chinese tree shrew, the total score of G-factor was found to be -0.66 that was generally larger than the acceptable value. This approach suggests the significance and acceptability of the modeled structure of CD59 of Chinese tree shrew. The molecular model data in cooperation to other relevant post model analysis data put forward molecular insight into protecting activity of CD59 protein molecule of Chinese tree shrew. Conclusion: In the present study, we have proposed the first molecular model structure of uncharted CD59 of Chinese tree shrew by significantly utilizing the comparative composite modeling approach. Therefore, the development of a structural model of the CD59 protein was carried out and analyzed further for deducing molecular enrichment technique. The collaborative effort of molecular model and other relevant data of post model analysis carry forward molecular understanding to protecting activity of CD59 functions towards better insight of features of this natural lead compound.

Background: Factor Xa (FXa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive targets for oral anticoagulants of new generation. Objective: Our approach for the development of directly acting oral anticoagulants (DOAC), FXa inhibitors was demonstrated in this work. Method: Chemical synthesis is the base of our approach for the development of potential inhibitors. In this work, the substances like R1-(CONH)-R2-(CONH)-R3 are being developed, using previously described docking and screening methods, where R1, R2 and R3 are some chemical groups and (CONH) are amide bonds connecting R1, R2 and R3. The direction of amide bond (CONH) could be arbitrary for R1, R2 and R2, R3. Results: Chemical modifications were made in the frame of the results, taking into account the structure of FXa, chemical synthesis capabilities, as well as patentability of the target compounds. Subnanomolar potency of several developed compounds was achieved. Several analyzers and various testing-suites have been used to measure the concentration that doubled the prothrombin time (PTx2). Moreover, in human plasma the PTx2 concentration of the compound 217 (DD217) turned out to be 80±20 nM. The compound efficacy has proved by in vivo assays including oral administrations in rats, rabbits and monkeys. Conclusion: The pharmacodynamic profile of DD217 for oral administration in cynomolgus monkeys proves the efficacy of the compound, which makes it promising for the future preclinical trials.

Background: Aspirin combination is prescribed for its thrombolytic activity where gastric ulceration is the major side effect of aspirin which can be prevented by combining it with proton pump inhibitor omeprazole. Present study describes development of analytical method for the estimation of aspirin and omeprazole in combination. Objective: The aim of the present study was to develop and validate chromatographic method for simultaneous analysis of aspirin and omeprazole. Methods: Isocratic, reversed phase stability indicating liquid chromatographic method was developed for the simultaneous determination of Aspirin and Omeprazole in combination. The separation was achieved on a Thermo Scientific Hypersil ODS (250 x 4.6 mm, 5 μm) column, kept at ambient temperature, using acetonitrile: methanol: 0.05 M phosphate buffer (40:5:55; pH 4 adjusted with 0.1% tri ethyl amine) as a mobile phase at a flow rate of 1 mL/min and UV detection was performed at 225 nm. Results: The retention time was found to be 3.9 min for aspirin and 5.3 min for omeprazole. The method was observed to be linear in the range of 2 - 80 μg/mL for aspirin and 1 - 40 μg/mL for omeprazole, respectively. The proposed method was validated as per ICH guidelines Q2 (R1). The developed RP- HPLC method was successfully applied for the simultaneous estimation of aspirin and omeprazole in the presence of degradation products of both the drugs. Conclusion: The present study describes liquid chromatographic method for the estimation of aspirin and omeprzole in combination. The method can be used for the analysis of stability samples and routine quality control samples.