Formulation Strategies and Practice Used for Drug Candidates with Water-Insoluble Properties for Toxicology, Biology, and Pharmacology Studies in Discovery Support

2008 ◽  
pp. 113-132
Author(s):  
Shyam Karki ◽  
Orn Almarsson ◽  
Lian-Feng Huang ◽  
Jinquan Dong
Keyword(s):  
Drug Candidates

Bringing Biocatalysis into the Deuteration Toolbox

2019 ◽  
Author(s):  
Jack Rowbotham ◽  
Oliver Lenz ◽  
Holly Reeve ◽  
Kylie Vincent
Keyword(s):  
Late Stage ◽  
Hydrogen Isotope ◽  
Reductive Amination ◽  
Mechanistic Studies ◽  
Ambient Conditions ◽  
Synthetic Pathway ◽  
Drug Candidates ◽  
Isotopic Selectivity ◽  
Reducing Equivalents

<p></p><p>Chemicals labelled with the heavy hydrogen isotope deuterium (<sup>2</sup>H) have long been used in chemical and biochemical mechanistic studies, spectroscopy, and as analytical tracers. More recently, demonstration of selectively deuterated drug candidates that exhibit advantageous pharmacological traits has spurred innovations in metal-catalysed <sup>2</sup>H insertion at targeted sites, but asymmetric deuteration remains a key challenge. Here we demonstrate an easy-to-implement biocatalytic deuteration strategy, achieving high chemo-, enantio- and isotopic selectivity, requiring only <sup>2</sup>H<sub>2</sub>O (D<sub>2</sub>O) and unlabelled dihydrogen under ambient conditions. The vast library of enzymes established for NADH-dependent C=O, C=C, and C=N bond reductions have yet to appear in the toolbox of commonly employed <sup>2</sup>H-labelling techniques due to requirements for suitable deuterated reducing equivalents. By facilitating transfer of deuterium atoms from <sup>2</sup>H<sub>2</sub>O solvent to NAD<sup>+</sup>, with H<sub>2</sub> gas as a clean reductant, we open up biocatalysis for asymmetric reductive deuteration as part of a synthetic pathway or in late stage functionalisation. We demonstrate enantioselective deuteration via ketone and alkene reductions and reductive amination, as well as exquisite chemo-control for deuteration of compounds with multiple unsaturated sites.</p><p></p>

Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids

2019 ◽  
Author(s):  
Ming Shang ◽  
Karla S. Feu ◽  
Julien C. Vantourout ◽  
Lisa M. Barton ◽  
Heather L. Osswald ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Heterocyclic Compounds ◽  
Cross Coupling ◽  
Building Blocks ◽  
Enantioselective Synthesis ◽  
Carbon Centers ◽  
Drug Candidates ◽  
Rapid Diversification ◽  
Directing Group ◽  
Compound Series

<div> <div> <div> <p>The union of two powerful transformations, directed C–H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series. </p> </div> </div> </div>

Recent Advances in Obesity: The Role of Turmeric Tuber and Its Metabolites in the Prophylaxis and Therapeutical Strategies

2019 ◽  
Vol 25 (37) ◽  
pp. 4837-4853 ◽  
Author(s):  
Agata Jarząb ◽  
Wirginia Kukula-Koch
Keyword(s):  
Body Weight ◽  
21St Century ◽  
The Body ◽  
Excess Body Weight ◽  
Inflammatory Reactions ◽  
Drug Candidates ◽  
Scientific Papers ◽  
Important Health ◽  
High Concern

Background: Obesity in the 21st century society became an important health problem, alarming both the scientists and medicine doctors around the world. That is why, the search for new drug candidates capable to reduce the body weight is of high concern. Objective: This contribution tends to collect current findings on the biochemistry of obesity and on the application of plants and in particular turmeric tuber – a commonly used spice - as an anti-obesity agent. Methods: Following an introduction on the biochemical characteristics of obesity, the description of Curcuma secondary metabolites, their pharmacological applications and a study on the plants’ regulatory properties in obesity was summarized. Particular attention was paid to curcumin – the major metabolite present in the extracts of Curcuma spp., which is known to exhibit a variety of pharmacological actions. Also, the characteristics of some semisynthetic analogues of this ferulic acid derivative, characterized by a higher polarity and better bioavailability will be discussed. Results: Numerous scientific papers treat on the influence of turmeric on weight loss. Additionally, some of them describe its anti-inflammatory properties. Conclusions: This important spice tends to fight the 21st century plague, which is an excessive weight gain, related to the development of metabolic syndrome, to the occurrence of cardiovascular problems and diabetes, and, in consequence, leading to a significant shortening of life span. As herein proven, the extracts of turmeric play an important role in the regulation of inflammatory reactions which are evoked in the overweight patients, helping them reduce the excess body weight.

Antitubercular Marine Natural Products

2018 ◽  
Vol 25 (20) ◽  
pp. 2304-2328 ◽  
Author(s):  
Lishu Wang ◽  
Jungfeng Wang ◽  
Juan Liu ◽  
Yonghong Liu
Keyword(s):  
Natural Products ◽  
Marine Natural Products ◽  
Antitubercular Activity ◽  
Marine Resources ◽  
Drug Candidates ◽  
New Drug ◽  
Chemical Constitution

Due to the importance of nature as a source of new drug candidates, the purpose of this article is to emphasize the marine natural products, which exhibit antitubercular activity, published between January 2000 and May 2016, with 138 quotations to 250 compounds obtained from marine resources. These metabolites are organized by chemical constitution and named as simple alkyl lipids derivatives, aromatics derivatives, peptides, alkaloids, terpenoids, steroids, macrolides, and polycyclic polyketides.

Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

2018 ◽  
Vol 25 (21) ◽  
pp. 2503-2519 ◽  
Author(s):  
Anne Kokel ◽  
Marianna Torok
Keyword(s):  
Side Effects ◽  
Antimicrobial Peptides ◽  
Potential Drug ◽  
Green Technologies ◽  
Specific Antibodies ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Induce Resistance ◽  
Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics

2018 ◽  
Vol 25 (5) ◽  
pp. 636-658 ◽  
Author(s):  
Jan Pokorny ◽  
Lucie Borkova ◽  
Milan Urban
Keyword(s):  
Biological Activities ◽  
Synthetic Approach ◽  
Clinical Use ◽  
New Approach ◽  
Click Reactions ◽  
Drug Candidates ◽  
The Past ◽  
Low Toxicity ◽  
New Compounds ◽  
Potential Therapeutics

Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

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