Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

Natural products from Brazilian biodiversity as a source of new models for medicinal chemistry

2012 ◽  
Vol 84 (9) ◽  
pp. 1837-1846 ◽  
Author(s):  
Vanderlan da Silva Bolzani ◽  
Marilia Valli ◽  
Marcos Pivatto ◽  
Cláudio Viegas
Keyword(s):  
Natural Products ◽  
Combinatorial Chemistry ◽  
Medicinal Chemistry ◽  
Therapeutic Agents ◽  
Molecular Structures ◽  
Biologically Active ◽  
Ache Inhibitors ◽  
Tropical Environments ◽  
Modern Drug ◽  
Brazilian Biodiversity

Natural products are the inspiration for many valuable therapeutic agents and attest to biodiversity being a rich source of new molecular structures. Their value as templates for medicinal chemistry remains undisputed, even after the growth of the combinatorial chemistry era. Tropical environments, such as Brazilian biomes, offer a particularly rich potential for biologically active compounds with unique structures and continue to contribute toward modern drug discovery. Our bioprospecting of plant species of the Cerrado and Atlantic Forest biomes has yielded promising bioactive secondary metabolites, and we describe some of these molecules and semisynthetic derivatives as potential acetylcholinesterase (AChE) inhibitors.

Coumarin Compounds in Medicinal Chemistry: Some Important Examples from the Last Years

2018 ◽  
Vol 18 (2) ◽  
pp. 124-148 ◽  
Author(s):  
Thiago Moreira Pereira ◽  
Daiana Portella Franco ◽  
Felipe Vitorio ◽  
Arthur Eugen Kummerle
Keyword(s):  
Medicinal Chemistry ◽  
Chemical Space ◽  
Noncovalent Interactions ◽  
Biological Activities ◽  
Fluorescent Sensors ◽  
Coumarin Derivatives ◽  
Research Projects ◽  
Wide Range ◽  
Coumarin Compounds ◽  
Treatment And Diagnosis

Coumarins are natural products characterized as 1,2 benzopyrones widely distributed in plants, as well as, in many species of fungi and bacteria. Nowadays, many synthetic procedures allow the discovery of coumarins with expanded chemical space. The ability to exert noncovalent interactions with many enzymes and receptors in live organisms lead the coumarins to exhibit a wide range of biological activities and applications. Then, this manuscript provides an overview of the use of coumarins compounds in medicinal chemistry in treating many diseases. Important examples of the last years have been selected concerning the activities of coumarins as anticoagulant, anticancer, antioxidant, antiviral, anti-diabetics, anti-inflammatory, antibacterial, antifungal and anti-neurodegerative agents. Additionally, it also includes applications of coumarins as fluorescent sensors for biological systems. Thus, this work aims to contribute to the development of new rational research projects for the treatment and diagnosis of pathologies using coumarin derivatives.

Abiotic scaffolds in medicinal chemistry: not a waste of chemical space

2021 ◽  
Vol 13 (2) ◽  
pp. 211-224
Author(s):  
Ronald W Brown
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Systems ◽  
Chemical Entity ◽  
Complex Chemical ◽  
Bioactive Natural Products ◽  
Gray Area ◽  
3D Topology

It is well established that medicinal chemists should depart from the flat, sp2-dominated nature of traditional drugs and incorporate complexities of bioactive natural products, such as sp3-richness, 3D topology and chirality. There is a gray area, however, in the relevance of newly developed chemical scaffolds that exhibit these complexities but do not correlate to anything observed in nature. This can leave synthetic methodologists searching for structural similarities between their newly developed products and known natural products in search of justification. This article offers a perspective on how these types of complex ‘abiotic' scaffolds can be appreciated purely on the basis of their structural novelty, and identifies the unique advantages arising when a complex chemical entity unrecognized by nature is introduced to biological systems.

scholarly journals Targeted Isolation of Rubrolides from the New Zealand Marine Tunicate Synoicum kuranui

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 337
Author(s):  
Joe Bracegirdle ◽  
Luke J. Stevenson ◽  
Michael J. Page ◽  
Jeremy G. Owen ◽  
Robert A. Keyzers
Keyword(s):  
Natural Products ◽  
Bacillus Subtilis ◽  
New Zealand ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Chemical Space ◽  
Gram Positive Bacteria ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
New Chemical Entities

Global natural products social (GNPS) molecular networking is a useful tool to categorize chemical space within samples and streamline the discovery of new natural products. Here, we demonstrate its use in chemically profiling the extract of the marine tunicate Synoicum kuranui, comprised of many previously reported rubrolides, for new chemical entities. Within the rubrolide cluster, two masses that did not correspond to previously reported congeners were detected, and, following MS-guided fractionation, led to the isolation of new methylated rubrolides T (3) and (Z/E)–U (4). Both compounds showed strong growth inhibitory activity against the Gram-positive bacteria Bacillus subtilis, with minimum inhibitory concentration (MIC) values of 0.41 and 0.91 μM, respectively.

scholarly journals Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

2016 ◽  
Vol 113 (42) ◽  
pp. E6343-E6351 ◽  
Author(s):  
Michael A. Skinnider ◽  
Chad W. Johnston ◽  
Robyn E. Edgar ◽  
Chris A. Dejong ◽  
Nishanth J. Merwin ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Sequencing ◽  
Sequence Data ◽  
Chemical Space ◽  
Biological Activities ◽  
Global Analysis ◽  
Gene Clusters ◽  
Systematic Investigation ◽  
Chemical Structures ◽  
Modified Peptides

Microbial natural products are an evolved resource of bioactive small molecules, which form the foundation of many modern therapeutic regimes. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) represent a class of natural products which have attracted extensive interest for their diverse chemical structures and potent biological activities. Genome sequencing has revealed that the vast majority of genetically encoded natural products remain unknown. Many bioinformatic resources have therefore been developed to predict the chemical structures of natural products, particularly nonribosomal peptides and polyketides, from sequence data. However, the diversity and complexity of RiPPs have challenged systematic investigation of RiPP diversity, and consequently the vast majority of genetically encoded RiPPs remain chemical “dark matter.” Here, we introduce an algorithm to catalog RiPP biosynthetic gene clusters and chart genetically encoded RiPP chemical space. A global analysis of 65,421 prokaryotic genomes revealed 30,261 RiPP clusters, encoding 2,231 unique products. We further leverage the structure predictions generated by our algorithm to facilitate the genome-guided discovery of a molecule from a rare family of RiPPs. Our results provide the systematic investigation of RiPP genetic and chemical space, revealing the widespread distribution of RiPP biosynthesis throughout the prokaryotic tree of life, and provide a platform for the targeted discovery of RiPPs based on genome sequencing.

Recent Applications of Benzimidazole as a Privileged Scaffold in Drug Discovery

2020 ◽  
Vol 20 ◽  
Author(s):  
Yongzhen Guo ◽  
Xuben Hou ◽  
Hao Fang
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Anticancer Agents ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Great Influence ◽  
Parasitic Infections ◽  
Peptic Ulcers ◽  
Lead Compounds ◽  
Privileged Scaffold

: Benzimidazole is an aromatic bicyclic heterocycle that is regarded as a valuable privileged scaffold in medicinal chemistry. Many marketed drugs and natural products containing benzimidazole scaffolds exert great influence in fighting various diseases, such as hypertension, peptic ulcers, parasitic infections, and cancer. In this review, we introduce the pharmacological applications of some marketed drugs and lead compounds with a focus on anticancer agents, reporting the corresponding data to show the biological activities at their targets. The publications in this review encompass those from 2014 to 2019.

scholarly journals A Promiscuous Halogenase for the Derivatization of Flavonoids

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6220
Author(s):  
Dominik Kolling ◽  
Marc Stierhof ◽  
Constanze Lasch ◽  
Maksym Myronovskyi ◽  
Andriy Luzhetskyy
Keyword(s):  
Natural Products ◽  
Biological Activities ◽  
Substrate Recognition ◽  
Pharmaceutical Research ◽  
Homology Model ◽  
Downstream Processing ◽  
Modern Drug ◽  
Frankia Alni ◽  
Synthetic Approaches ◽  
Drug Leads

Halogenation often improves the bioactive properties of natural products and is used in pharmaceutical research for the generation of new potential drug leads. High regio- and stereospecificity, simple reaction conditions and straightforward downstream processing are the main advantages of halogenation using enzymatic biocatalysts compared to chemical synthetic approaches. The identification of new promiscuous halogenases for the modification of various natural products is of great interest in modern drug discovery. In this paper, we report the identification of a new promiscuous FAD-dependent halogenase, DklH, from Frankia alni ACN14a. The identified halogenase readily modifies various flavonoid compounds, including those with well-studied biological activities. This halogenase has been demonstrated to modify not only flavones and isoflavones, but also flavonols, flavanones and flavanonols. The structural requirements for DklH substrate recognition were determined using a feeding approach. The homology model of DklH and the mechanism of substrate recognition are also proposed in this paper.

scholarly journals A Chemometric Analysis of Deep-Sea Natural Products

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3942 ◽  
Author(s):  
Pilkington
Keyword(s):  
Natural Products ◽  
Deep Sea ◽  
Chemical Space ◽  
Biological Activities ◽  
Significant Proportion ◽  
Biologically Active ◽  
Challenging Environment ◽  
Bacteria And Fungi ◽  
Promising Source ◽  
Potential Therapeutics

Deep-sea natural products have been created by unique marine organisms that thrive in a challenging environment of extreme conditions for its inhabitants. In this study, 179 deep-sea natural products isolated from 2009 to 2013 were investigated by analysing their physicochemical properties that are important indicators of the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile of a compound. The study and analysis of these molecular descriptors and characteristics enabled the defining of these compounds in various chemical spaces, particularly as an indication of their drug-likeness and position in chemical space and is the first to be conducted to analyse deep-sea derived natural products. It was found that ~40% of all deep-sea natural products were drug-like and 2/3 were within Known Drug Space (KDS), highlighting the high drug-likeness of a significant proportion of deep-sea natural products, most of which have already been shown to have notable biological activities, that should be further investigated as potential therapeutics. Furthermore, this study was able to reveal the general structural differences between compounds from Animalia, Bacteria and Fungi organisms where it was observed that natural products from members of the Animalia kingdom are structurally more varied than compounds from bacteria and fungi. It was also noted that, in general, fungi-derived compounds occupy a more favourable position in drug-like chemical space and are a rich and promising source of biologically-active natural products for the purposes of drug development and therapeutic application.

scholarly journals Towards a systematic map of the functional role of protein phosphorylation

2019 ◽  
Author(s):  
Cristina Viéitez ◽  
Bede P. Busby ◽  
David Ochoa ◽  
André Mateus ◽  
Marco Galardini ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Systematic Map ◽  
Gene Deletions ◽  
Chemical Genetic ◽  
Cellular Processes ◽  
Growth Profiles ◽  
Functional Relevance ◽  
Almost All

AbstractPhosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phosphomutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.

scholarly journals Thoughts on Natural Medicinal Chemistry

2019 ◽  
Vol 8 (3) ◽  
pp. 29-34
Author(s):  
Xing Peng ◽  
Meilan Li
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Lead Compounds ◽  
Drug Lead ◽  
Novel Structures

Natural products, with novel structures and broad biological activities, are the main sources of drug lead compounds. Over years, natural products have made outstanding contributions to the fight against viruses. Herein, the article briefly shares some thoughts about natural medicinal chemistry as references for chemists and biologists.

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