Current Topics in Medicinal Chemistry - Volume 19, Issue 5, 2019

Drug-drug interaction (DDI) is the phenomenon of alteration of the pharmacological activity of a drug(s) when another drug(s) is co-administered in cases of so-called polypharmacy. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent type of DDI, which often appears as a result of the inhibition or induction of drug-metabolising enzymes (DME). In this review, we summarise in silico methods that may be applied for the prediction of the inhibition or induction of DMEs and describe appropriate computational methods for DDI prediction, showing the current situation and perspectives of these approaches in medicinal and pharmaceutical chemistry. We review sources of information on DDI, which can be used in pharmaceutical investigations and medicinal practice and/or for the creation of computational models. The problem of the inaccuracy and redundancy of these data are discussed. We provide information on the state-of-the-art physiologically- based pharmacokinetic modelling (PBPK) approaches and DME-based in silico methods. In the section on ligand-based methods, we describe pharmacophore models, molecular field analysis, quantitative structure-activity relationships (QSAR), and similarity analysis applied to the prediction of DDI related to the inhibition or induction of DME. In conclusion, we discuss the problems of DDI severity assessment, mention factors that influence severity, and highlight the issues, perspectives and practical using of in silico methods.

Tuberculosis (TB) still continues to be a major killer disease worldwide. Unlike other bacteria Mycobacterium tuberculosis (Mtb) has the ability to become dormant within the host and to develop resistance. Hence efforts are being made to overcome these problems by searching for new antitubercular agents which may be useful in the treatment of multidrug-(MDR) and extensively drugresistant (XDR) M. tuberculosis and shortening the treatment time. The recent introduction of bedaquiline to treat MDR-TB and XDR-TB may improve the status of TB treatment. The target enzymes in anti-TB drug discovery programs play a key role, hence efforts have been made to review the work on molecules including antiTB drugs acting on different enzyme targets including ATP synthase, the target for bedaquiline. Literature searches have been carried out to find the different chemical molecules including drugs and their molecular targets responsible for their antitubercular activities in recent years. This review provides an overview of the chemical structures with their antitubercular activities and enzyme targets like InhA, ATP synthase, Lip Y, transmembrane transport protein large (MmpL3), and decaprenylphospho-β-D-ribofuranose 2-oxidase, (DprE1). The major focus has been on the new target ATP synthase. Such an attempt may be useful in designing new chemical entities (NCEs) for specific and multi-drug targeting against Mtb.

Background: Thiazole derivates as well as chalcones, are very important scaffold for medicinal chemistry. Literature survey revealed that they possess wide spectrum of biological activities among which are anti-inflammatory and antimicrobial. Objectives: The current studies describe the synthesis and evaluation of antimicrobial activity of twenty eight novel thiazole-based chalcones. Methods: The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. Results: All compounds have shown antibacterial properties better than that of ampicillin and in many cases better than streptomycin. As far as the antifungal activity is concerned, all compounds possess much higher activity than reference drugs bifonazole and ketoconazole. The most sensitive bacterial species was B. cereus (MIC 6.5-28.4 μmol 10-2/mL and MBC 14.2-105.0 μmol 10-2/mL) while the most resistant ones were L. monocytogenes (MIC 21.4-113.6 μmol 10-2/mL) and E. coli (MIC 10.7- 113.6 μmol 10-2/mL) and MBC at 42.7-358.6 μmol 10-2/mL and 21.4-247.2 μmol 10-2/mL, respectively. All the compounds exhibited antibacterial activity against the three resistant strains, MRSA, P. aeruginosa and E.coli. with MIC and MBC in the range of 0.65-11.00 μmol/mL 10-2 and 1.30-16.50 μmol/mL 10-2. Docking studies were performed. Conclusion: Twenty-eight novel thiazole-based chalcones were designed, synthesized and evaluated for antimicrobial activity. The results showed that these derivatives could be lead compounds in search of new potent antimicrobial agents. Docking studies indicated that DNA gyrase, GyrB and MurA inhibition may explain the antibacterial activity.

Background & Objective: Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively. Methods: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH. Results: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02μM and 1 ± 0.03 μM, respectively. Conclusion: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.

Background: The main characteristic of Diabetes type II is the impaired activation of intracellular mechanisms triggered by the action of insulin. PTP1b is a Protein Tyrosine Phosphatase that dephosphorylates insulin receptor causing its desensitization. Since inhibition of PTP1b may prolong insulin receptor activity, PTP1b has become a drug target for the treatment of Diabetes II. Although a number of inhibitors have been synthesized during the last decades, the research still continues for the development of more effective and selective compounds. Moreover, several constituents of plants and edible algae with PTP1b inhibitory action have been found, adding this extra activity at the pallet of properties of the specific natural products. Objective: Sideritis L. (Lamiaceae) is a herbal plant growing around the Mediterranean sea which is included in the Mediterranean diet for centuries. The present study is the continuation of a previous work where the antioxidant and anti-inflammatory activities of the components of Sideritis L. were evaluated and aimed to investigate the potential of some sideritis’s components to act as PTP1b inhibitors, thus exhibiting the beneficial effect in the treatment of diabetes II. Methods: Docking analysis was done to predict PTP1b inhibitory action. Human recombinant PTP1b enzyme was used for the evaluation of the PTP1b inhibitory action, while inhibition of the human LAR and human T-cell PTP was tested for the estimation of the selectivity of the compounds. Conclusion: Docking analysis effectively predicted inhibition and mode of inhibitory action. According to the experimental results, four of the components exhibited PTP1b inhibitory action. The most active ones were acetoside, which acted as a competitive inhibitor, with an IC50 of 4 μM and lavandufolioside, which acted as an uncompetitive inhibitor, with an IC50 of 9.3 μM. All four compounds exhibited increased selectivity against PTP1b.