Current Drug Discovery Technologies - Volume 15, Issue 1, 2018

Human Immunodeficiency Virus Type 1 Integrase or HIV-1 integrase (IN) is a 288 amino acid protein that incorporates the retrotranscribed viral DNA into the host chromosomal DNA. Over the past 30 years, large number of derivatives have been evaluated for their inhibitory potential against IN. There is vast literature available which need to be collated to help scientists plan the future drug design. This review discusses the reports of past 25 years on analogs of quinoline, coumarin and other related heterocycles, which exhibit low micromolar inhibitory potency against IN.

Background: Pressure ulcer remains as a common problem, especially developed in disabled patients and hence, subjected to continuous pressure for prolonged periods of time. Most of the studies investigating the preventive and therapeutic approaches have focused on wound cleansing, dressing and supportive strategies, as well as pharmacological therapy including zinc sulphate, vitamin A or phenytoin. Despite such efforts, pressure ulcer continues to impair the life quality and expectancy. Thus involving in the paradigm shift in biomedical studies, the recent ones focus on biological signaling pathways involving nitric oxide (NO)- soluble guanylatecyclase (sGC)- cyclic guanosine monophosphate (cGMP) contributing in vasodilation, reperfusion and oxygen delivery. Methods: Literatures review focusing on NO/sGC/cGMP pathway was performed as well as seeking themolecular biology aspects inKyoto Encyclopedia of genes and genomes (KEGG). Results: NO is an important signaling molecule activating sGC and cGMP production, which is a mediator of vasodilation and platelet inhibition. Considering the subject, it could be hypothesized that the application of sGC stimulators and activators is a very curious strategy for pressure ulcer healing. It is well known that pressure and shear forces usually produce the blood vessel obstruction, inducing ischemia and tissue necrosis and in pathologic states, damaged endothelium leads to a reduced synthesis of NO and inadequate oxygen supply contributing to delayed wound healing. Riociguat is the first FDA approved agent of new class of sGC stimulators, involving in activation of sGC both in presence and absence of NO. Conclusion: The findings of this review confirm that Riociguat could start a new therapeutic approach for pressure ulcer treatment even with dysfunctional endothelium.

Background: Chronic hepatitis C virus (HCV) is a worldwide health problem that can lead to liver cirrhosis, liver cell failure and numerous subsequent complications such as hepatocellular carcinoma. Till the near past, pegylated interferon was the standard of care therapy. However, it was associated with suboptimal success rates and many side effects. Thereafter, direct antiviral agents (DAA) appeared and played the key role in management of HCV. One of those recent DAAs is ravidasvir. Summary: It is a potent NS5A inhibitor that was formerly known as PPI-668. It is produced by the cooperation of Presidio pharmaceuticals and Pharco International pharmaceutical company. Since its first production, it has been enrolled in different successive clinical trials. Phase 1 and 2 trials confirmed its safety and tolerability and its great efficacy in suppressing viral loads in short periods. It has a pangenotypic activity with favorable pharmacokinetic properties. Ravidasvir inhibits the replication of HCV variants that develop resistance mutations for different DAA classes. Even more, HCV variants that had reduced susceptibility to ravidasvir are completely susceptible to other DAA. Finally, a large multicenteric registrational phase 3 clinical trial that included large percentages of difficult to treat patients (such as cirrhotic and interferon experienced patients) has been fully accomplished and proved great SVR12 rates. Conclusion: Ravidasvir is a potent new NS5A inhibitor with excellent safety and tolerability in management of genotype 4 HCV patients.

Background: Despite the newly treatment procedures, cancer is considered as the main health threat nowadays and, therefore, new therapeutic options such as traditional medicine should be investigated. Rosemary (Rosmarinus officinalis L.) has been found to possess antitumor effects due to its major ingredients, including carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Objective: This study was designed to gather the recent literature findings from 2010 to 2016 on the cancer anti-tumor activities of carnosol and probably involved mechanisms. Method: The online English papers were gathered through various search websites, including PubMed, Iran Medex, Medline, Google Scholar, and Scopus from 2010 to 2016. Results: Carnosol, the specific composition of rosemary, has been shown to have beneficial effects in keeping humans healthy and may be acted as an antitumor agent. Conclusion: This review revealed that carnosol may be effective as an anti-tumor agent in the different types of cancer by inducing apoptosis and inhibiting the cell cycle division. However, more studies are needed to confirm carnosol therapeutic effects in human.

Background: Glycogen phosphorylase (GP) is a pharmaceutical target for the discovery of new antihyperglycaemic agents. Punica granatum is a well-known plant for its potent antioxidant and antimicrobial activities but so far has not been examined for antihyperglycaemic activity. Objective: The aim was to examine the inhibitory potency of eighteen polyphenolic extracts obtained from Punica granatum fruits and industrial juicing byproducts against GP and discover their most bioactive ingredients. Method: Kinetic experiments were conducted to measure the IC50 values of the extracts while affinity crystallography was used to identify the most bioactive ingredient. The inhibitory effect of one of the polyphenolic extracts was also verified ex vivo, in HepG2 cells. Results: All extracts exhibited significant in vitro inhibitory potency (IC50 values in the range of low μg/mL). Affinity crystallography revealed that the most bioactive ingredients of the extracts were chlorogenic and ellagic acids, found bound in the active and the inhibitor site of GP, respectively.While ellagic acid is an established GP inhibitor, the inhibition of chlorogenic acid is reported for the first time. Kinetic analysis indicated that chlorogenic acid is an inhibitor with Ki=2.5 x 10-3Mthat acts synergistically with ellagic acid. Conclusion: Our study provides the first evidence for a potential antidiabetic usage of Punica granatum extracts as antidiabetic food supplements. Although, more in vivo studies have to be performed before these extracts reach the stage of antidiabetic food supplements, our study provides a first positive step towards this process.

Background: High performance liquid chromatography is an integral analytical tool in assessing drug product stability. HPLC methods should be able to separate, detect, and quantify the various drug-related degradants that can form on storage or manufacturing, plus detect any drug-related impurities that may be introduced during synthesis. Objective: A simple, economic, selective, precise, and stability-indicating HPLC method has been developed and validated for analysis of Rifampicin (RIFA) and Piperine (PIPE) in bulk drug and in the formulation. Method: Reversed-phase chromatography was performed on a C18 column with Buffer (Potassium Dihydrogen Orthophosphate) pH 6.5 and Acetonitrile, 30:70), (%, v/v), as mobile phase at a flow rate of 1 mL min-1. Result: The detection was performed at 341 nm and sharp peaks were obtained for RIFA and PIPE at retention time of 3.3 ± 0.01 min and 5.9 ± 0.01 min, respectively. The detection limits were found to be 2.385 ng/ml and 0.107 ng/ml and quantification limits were found to be 7.228ng/ml and 0.325ng/ml for RIFA and PIPE, respectively. The method was validated for accuracy, precision, reproducibility, specificity, robustness, and detection and quantification limits, in accordance with ICH guidelines. Conclusion: Stress study was performed on RIFA and PIPE and it was found that these degraded sufficiently in all applied chemical and physical conditions. Thus, the developed RP-HPLC method was found to be suitable for the determination of both the drugs in bulk as well as stability samples of capsule containing various excipients.

Background: In Alzheimer's disease (AD), the gene mutations have been identified in the amyloid precursor protein (APP), the presenilin-1 (PS1) and -2 (PS2) genes. APP is a transmembrane protein which gets cleaved by α- and β- secretase enzymes and releases Aβ peptides which forms senile plaques in brain tissue. It contributes for local inflammatory response, subsequent oxidative stress, biochemical changes and neuronal death. Targeting the development of Aβ aggregates in the senile plaques is an important strategy in the treatment of AD. To facilitate the normal processing of APP, some of the reported approaches are stimulation of α- secretase activity or the modulation/inhibition of the β- and γ-secretase complex. Methods: The mechanism of γ–secretase inhibition is targeted based on the QSAR and molecular docking methods. The series based on 3-chloro-2-hydroxymethylbenzenesulfonamide was selected for in silico ligand-based modeling. Significant correlations, between their γ-Secretase inhibitory profile and 2D-descriptors, were obtained through multiple linear regression (MLR) computational procedure. Results: During QSAR nalysis, calculated molar refractivity (CMR) and surface tension (ST) were found to be contributing parameters along with halogen substituent at a particular position. Applicability analysis revealed that the suggested models have acceptable predictability (rpred 2 = 0.827). Conclusion: The inferences drawn from MLR were utilized to prepare a data set of fourteen substituted benzenesulfonamides (N1-N14). The in silico studies provides strong impetus towards systematic application of such methods during lead identification and optimization.