Recent Innovations of Organo-Fluorine synthesis and pharmacokinetics

: The fluorinated compounds have significance in medicinal chemistry and pharmaceuticals research. The introduction of fluorine atom in the heterocyclic compounds increases biological activity, develops favourable physiochemical interaction. Combination of the heterocycles and fluorine substituent having large scope in the research work of the different drugs molecules. The compounds not only show biological activity but also show unique physical and chemical properties that open the doors of multidisciplinary research areas. Fluorine atom tolerance towards maximum functional groups, simplicity in operation, replacing hydrogen with fluorine of bioactive molecules are more efficient for the production at the commercial level. The fluorine substitution also increases the binding affinity to the targeted protein. Also, incorporation of fluorine into the drug helps to increase the polarity hence to increase the rate of drug metabolism and improves the metabolic stability. The pharmacokinetic study plays an important role in clinical research, since 1996, researcher Whitford discover that the pharmacokinetic of fluorine is depend on its pH and amount in the bone. pH of organofluoride governs the absorption, distribution and excretion of fluoride. It also increases the stability when binding with carbon atom and resulting in an increase in bioactivity. This is the main reason that around 25% of present active drugs on various diseases, including cancer, diabetes, HIV, etc. have fluorine as important content. Not only pharmacokinetic property but also the physical property of the drug can be enhanced or altered by selective insertion at the key place of the fluorine atom in the drug compound. In this report, we have summarized the interesting research article reported since 2000 for the synthesis of low fluorine substituted organic compounds for medicinal research and pharmacokinetic study of fluorine molecules in neurological diseases, cancer, and tuberculosis research.

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Synthesis of 5-aryl-3-hydroxy-1-(2-hydroxypropyl)-4-(furyl-2-carbonyl)- 3-pyrrolin-2-ones and 5-aryl-3-hydroxy-1-(3-hydroxypropyl)- 4-(furyl-2-carbonyl)-3-pyrrolin-2-ones

Butlerov Communications ◽

10.37952/roi-jbc-01/20-63-9-26 ◽

2020 ◽

Vol 63 (9) ◽

pp. 26-30

Author(s):

Daria D. Rubtsova ◽

◽

Alexandra A. Bobyleva ◽

Daria D. Lezhnina ◽

Sofia V. Polikarpova ◽

...

Keyword(s):

Biological Activity ◽

1H Nmr ◽

Nmr Spectra ◽

Research Work ◽

Chemical Properties ◽

Methine Proton ◽

1H Nmr Spectra ◽

Biologically Active ◽

Hydroxyl Group ◽

Derivatives Of

In this work, pyrrolidin-2-ones and their derivatives are considered as a promising class of non-aromatic heterocyclic compounds. Their structure is found in the nuclei of many natural products and biologically active molecules. In pharmacy the possibility of introducing various substituents into the nucleus of pyrrolidin-2-ones is a great importance for the synthesis of new medicinal molecules with improved biological activity. Nowadays the synthesis of new active compounds by introducing various substituents at the C1-, C4- and C5-position of 3-hydroxy-3-pyrrolin-2-one has been little studied and it is of great interest to study the conditions of their synthesis, chemical properties and biological activity. In this research work the corresponding 5-aryl-3-hydroxy-1-(2-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones and 5-aryl-3-hydroxy-1-(3-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones were synthesized by the reaction of methyl ester of furyl-2-carbonylpyruvic acid with a mixture of aromatic aldehyde and 1-amino-2-hydroxypropane or 3-amino 1-hydroxypropane when heated in dioxane. The results of the study of the structure of the new synthesized compounds are presented. The structure was proved using 1H NMR spectroscopy and IR spectrometry. It was shown that the IR spectra of the compounds contain bands of the corresponding stretching vibrations of the alcoholic hydroxyl group, enol hydroxyl, amide and ketone groups. In the 1H NMR spectra of the compounds, along with the signals of aromatic protons in the C5 substituent and related groups, characteristic peaks are observed, indicating the formation of the corresponding derivatives of 3-hydroxy-3-pyrrolin-2-ones. It was noted that in the case of the synthesis of 5-aryl-3-hydroxy-1-(2-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones, the signal of the methine proton at the C5 position of the heterocycle is cleaved in 1H NMR spectra compounds as a result of the appearance of a second chiral center in the 2-hydroxypropyl radical. Elemental analysis was performed for the synthesized compounds.

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The Effect of Crosslinking Agents on the Properties of Type II Collagen Biomaterials

Materiale Plastice ◽

10.37358/mp.20.4.5416 ◽

2021 ◽

Vol 57 (4) ◽

pp. 166-180

Author(s):

Maria-Minodora Marin ◽

Madalina Georgiana Albu Kaya ◽

George Mihail Vlasceanu ◽

Jana Ghitman ◽

Ionut Cristian Radu ◽

...

Keyword(s):

Research Work ◽

Cartilage Tissue Engineering ◽

Chemical Properties ◽

Cartilage Regeneration ◽

Type Ii Collagen ◽

Biomechanical Properties ◽

Cartilage Tissue ◽

Cross Linking ◽

Type Ii ◽

Crosslinking Agents

Type II collagen has been perceived as the indispensable element and plays a crucial role in cartilage tissue engineering. Thus, materials based on type II collagen have drawn farther attention in both academic and research for developing new systems for the cartilage regeneration. The disadvantage of using type II collagen as a biomaterial for tissue repairing is its reduced biomechanical properties. This can be solved by physical, enzymatic or chemical cross-linking processes, which provide biomaterials with the required mechanical properties for medical applications. To enhance type II collagen properties, crosslinked collagen scaffolds with different cross-linking agents were prepared by freeze-drying technique. The present research work studied the synthesis of type II collagen biomaterials with and without crosslinking agents. Scaffolds morphology was observed by MicroCT, showing in all cases an appropriate microstructure for biological applications, and the mechanical studies were performed using compressive tests. DSC showed an increase in denaturation temperature with an increase in cross-linking agent concentration. FTIR suggested that the secondary structure of collagen is not affected after the cross-linking; supplementary, to confirm the characteristic triple-helix conformation of collagen, the CD investigation was performed. The results showed that the physical-chemical properties of type II collagen were improved by cross-linking treatments.

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Homologation: A Versatile Molecular Modification Strategy to Drug Discovery

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190808145235 ◽

2019 ◽

Vol 19 (19) ◽

pp. 1734-1750 ◽

Cited By ~ 2

Author(s):

Lídia M. Lima ◽

Marina A. Alves ◽

Daniel N. do Amaral

Keyword(s):

Protein Structure ◽

Homologous Series ◽

Molecular Conformation ◽

Chemical Properties ◽

Lead Optimization ◽

Pharmacokinetic Property ◽

Molecular Modification ◽

Physico Chemical ◽

Pharmacokinetic Properties ◽

Lead Identification

Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properties and molecular conformation are presented and discussed. Its application in lead-identification and lead optimization steps, as well as its impact on pharmacodynamics/pharmacokinetic properties and on protein structure is highlighted from selected examples. • Homologation: definition and types • Homologous series in nature • Comparative physico-chemical and conformational properties • Application in lead-identification and lead-optimization • Impact on pharmacodynamic property • Impact on pharmacokinetic property • Impact on protein structure • Concluding remarks • Acknowledgment • References

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Natural Compounds and Drug Discovery: Can Cnidarian Venom Play a Role?

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666190227234834 ◽

2019 ◽

Vol 19 (2) ◽

pp. 114-118

Author(s):

Gian Luigi Mariottini ◽

Irwin Darren Grice

Keyword(s):

Biological Activity ◽

Marine Species ◽

Natural Compounds ◽

Therapeutic Agents ◽

Industrial Applications ◽

Bioactive Molecules ◽

Sea Anemones ◽

Therapeutic Approaches ◽

Ongoing Research ◽

Biological Compounds

Natural compounds extracted from organisms and microorganisms are an important resource for the development of drugs and bioactive molecules. Many such compounds have made valuable contributions in diverse fields such as human health, pharmaceutics and industrial applications. Presently, however, research on investigating natural compounds from marine organisms is scarce. This is somewhat surprising considering that the marine environment makes a major contribution to Earth's ecosystems and consequently possesses a vast storehouse of diverse marine species. Interestingly, of the marine bioactive natural compounds identified to date, many are venoms, coming from Cnidarians (jellyfish, sea anemones, corals). Cnidarians are therefore particularly interesting marine species, producing important biological compounds that warrant further investigation for their development as possible therapeutic agents. From an experimental aspect, this review aims to emphasize and update the current scientific knowledge reported on selected biological activity (antiinflammatory, antimicrobial, antitumoral, anticoagulant, along with several less studied effects) of Cnidarian venoms/extracts, highlighting potential aspects for ongoing research towards their utilization in human therapeutic approaches.

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Isatin: A Scaffold with Innumerable Biodiversity

Mini-Reviews in Medicinal Chemistry ◽

10.2174/2211536609666201125115559 ◽

2020 ◽

Vol 20 ◽

Author(s):

Priyobrata Nath ◽

Agnish Mukherjee ◽

Sougata Mukherjee ◽

Sabyasachi Banerjee ◽

Samarpita Das ◽

...

Keyword(s):

Biological Effects ◽

Scientific Information ◽

Research Work ◽

Chemical Properties ◽

Industrial Applications ◽

Biologically Relevant ◽

Extensive Information ◽

Relevant Compound ◽

A Minor ◽

Clinical Conditions

: Isatin is an endogenous and a significant category of fused heterocyclic component, widely been a part of several potential biologically useful synthetics. Since its discovery, tons of research work has been conducted with respect to the synthesis, chemical properties, and biological and industrial applications. It contains indole nucleus having both lactam and keto moiety which while being a part of a molecular framework exerted several biological effects, viz.; antimicrobial, antitubercular, anticonvulsant, anticancer etc. Isatin derivatives are synthetically significant substrates, which can be utilized for the synthesis of huge diversified chemical entities of which few members emerged to be a drug. The reason for this review is to provide extensive information pertaining to the chemistry and its significance in altering several pathological states of isatin and its derivatives. A Structure Activity Relationships study thus developed through a gamut of scientific information indicates the importance of mostly electron withdrawing groups, halogens, nitro, alkoxy and to a minor extent groups with positive inductive effects, such as methyl at position 1, 5, 6 and 7 of isatin in alleviating several clinical conditions. It is also observed from the survey that the presence of two oxo groups at position 2 and 3 sometimes become insignificant as fusion with a heterocycle at those position resulted in a biologically relevant compound.

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Silver Nanoparticles Stabilized with Phosphorus-Containing Heterocyclic Surfactants: Synthesis, Physico-Chemical Properties, and Biological Activity Determination

Nanomaterials ◽

10.3390/nano11081883 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1883

Author(s):

Martin Pisárčik ◽

Miloš Lukáč ◽

Josef Jampílek ◽

František Bilka ◽

Andrea Bilková ◽

...

Keyword(s):

Silver Nanoparticles ◽

Biological Activity ◽

Zeta Potential ◽

Chain Length ◽

Alkyl Chain ◽

Chemical Properties ◽

Alkyl Chain Length ◽

Microbial Pathogens ◽

Physico Chemical ◽

Phosphorus Containing

Phosphorus-containing heterocyclic cationic surfactants alkyldimethylphenylphospholium bromides with the alkyl chain length 14 to 18 carbon atoms were used for the stabilization of silver nanodispersions. Zeta potential of silver nanodispersions ranges from +35 to +70 mV, which indicates the formation of stable silver nanoparticles (AgNPs). Long-chain heptadecyl and octadecyl homologs of the surfactants series provided the most intensive stabilizing effect to AgNPs, resulting in high positive zeta potential values and smaller diameter of AgNPs in the range 50–60 nm. A comparison with non-heterocyclic alkyltrimethylphosphonium surfactants of the same alkyl chain length showed better stability and more positive zeta potential values for silver nanodispersions stabilized with heterocyclic phospholium surfactants. Investigations of biological activity of phospholium-capped AgNPs are represented by the studies of antimicrobial activity and cytotoxicity. While cytotoxicity results revealed an increased level of HepG2 cell growth inhibition as compared with the cytotoxicity level of silver-free surfactant solutions, no enhanced antimicrobial action of phospholium-capped AgNPs against microbial pathogens was observed. The comparison of cytotoxicity of AgNPs stabilized with various non-heterocyclic ammonium and phosphonium surfactants shows that AgNPs capped with heterocyclic alkyldimethylphenylphospholium and non-heterocyclic triphenyl-substituted phosphonium surfactants have the highest cytotoxicity among silver nanodispersions stabilized by the series of ammonium and phosphonium surfactants.

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Difluorocarbene enables to access 2-fluoroindoles from ortho-vinylanilines

Nature Communications ◽

10.1038/s41467-021-25313-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianke Su ◽

Xinyuan Hu ◽

Hua Huang ◽

Yu Guo ◽

Qiuling Song

Keyword(s):

Fluorine Atom ◽

High Efficiency ◽

Addition Reaction ◽

Bond Cleavage ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

General Strategy ◽

Michael Addition Reaction ◽

Fundamental Properties ◽

Synthetic Approaches

Abstract2-Fluoroindoles as an important structural scaffold are widely existing in many bioactive or therapeutic agents. Despite their potential usefulness, efficient constructions of 2-fluoroindole derivatives are very sparce. The development of straightforward synthetic approaches to access 2-fluoroindoles is highly desirable for studying their fundamental properties and applications. Herein, we report an efficient and general strategy for the construction of 2-fluoroindoles in which a wide variety of 2-fluoroindoles were accessed with high efficiency and chemoselectivity. Instead of starting from indole skeletons, our strategy constructs indole scaffolds alongside the incorporation of fluorine atom on C2 position in a formal [4+1] cyclization from readily accessible ortho-vinylanilines and difluorocarbene. In our protocol, commercially accessible halodifluoroalkylative reagents provide one carbon and one fluorine atom by cleaving one C-N tertiary bond and forming one C-N bond and one C-C double bond with ortho-vinylanilines. Downstream transformations on 2-fluoroindoles lead to various valuable bioactive molecules which demonstrated significant synthetic advantages over previous reports. And mechanistic studies suggest that the reaction undergoes a cascade difluorocarbene-trapping and intramolecular Michael addition reaction followed by Csp3-F bond cleavage.

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Design and Synthesis of Fluoro Analogues of Vitamin D

International Journal of Molecular Sciences ◽

10.3390/ijms22158191 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8191

Author(s):

Fumihiro Kawagoe ◽

Sayuri Mototani ◽

Atsushi Kittaka

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Fluorine Atom ◽

Chemical Properties ◽

Molecular Structures ◽

Physical And Chemical Properties ◽

Design And Synthesis ◽

Synthetic Methodologies ◽

Physical And Chemical ◽

And Chemical Properties

The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.

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Functionalization of Cellulose-Based Hydrogels with Bi-Functional Fusion Proteins Containing Carbohydrate-Binding Modules

Materials ◽

10.3390/ma14123175 ◽

2021 ◽

Vol 14 (12) ◽

pp. 3175

Author(s):

Mariana Barbosa ◽

Hélvio Simões ◽

Duarte Miguel F. Prazeres

Keyword(s):

Fusion Proteins ◽

Fluorescent Protein ◽

Protein A ◽

Chemical Properties ◽

Main Idea ◽

Bioactive Molecules ◽

Scaffolding Protein ◽

Carbohydrate Binding ◽

Biological Interactions ◽

Carbohydrate Binding Modules

Materials with novel and enhanced functionalities can be obtained by modifying cellulose with a range of biomolecules. This functionalization can deliver tailored cellulose-based materials with enhanced physical and chemical properties and control of biological interactions that match specific applications. One of the foundations for the success of such biomaterials is to efficiently control the capacity to combine relevant biomolecules into cellulose materials in such a way that the desired functionality is attained. In this context, our main goal was to develop bi-functional biomolecular constructs for the precise modification of cellulose hydrogels with bioactive molecules of interest. The main idea was to use biomolecular engineering techniques to generate and purify different recombinant fusions of carbohydrate binding modules (CBMs) with significant biological entities. Specifically, CBM-based fusions were designed to enable the bridging of proteins or oligonucleotides with cellulose hydrogels. The work focused on constructs that combine a family 3 CBM derived from the cellulosomal-scaffolding protein A from Clostridium thermocellum (CBM3) with the following: (i) an N-terminal green fluorescent protein (GFP) domain (GFP-CBM3); (ii) a double Z domain that recognizes IgG antibodies; and (iii) a C-terminal cysteine (CBM3C). The ability of the CBM fusions to bind and/or anchor their counterparts onto the surface of cellulose hydrogels was evaluated with pull-down assays. Capture of GFP-CBM3 by cellulose was first demonstrated qualitatively by fluorescence microscopy. The binding of the fusion proteins, the capture of antibodies (by ZZ-CBM3), and the grafting of an oligonucleotide (to CBM3C) were successfully demonstrated. The bioactive cellulose platform described here enables the precise anchoring of different biomolecules onto cellulose hydrogels and could contribute significatively to the development of advanced medical diagnostic sensors or specialized biomaterials, among others.

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