Fluorination methods in drug discovery (original) (raw)
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Tactical Applications of Fluorine in Drug Design and Development
Fluorine in Heterocyclic Chemistry Volume 1, 2014
The increasing utilization of fl uorine in drug design parallels advances in understanding the physicochemical attributes of this element and an enhanced appreciation of how these unique properties can be exploited to address the numerous challenges encountered in pharmaceutical candidate optimization. Judicious placement of fl uorine in a candidate compound can markedly affect potency, increase metabolic stability and enhance membrane permeability. The powerful electron-withdrawing nature of fl uorine serves to modulate the p K a of proximal functionality, particularly basic amines, and can be an important tool for controlling physical properties. Fluorine also exerts a conformation bias that is signifi cant and can be utilized strategically. The 18 F isotope is of particular importance in positron
Important fluorinated drugs in experimental and clinical use Authors proof20200710 18110 1ige75f
This reviews details selected fluorine-containing drugs that either have potential for, or are already in, clinical use. Fluorine imparts desirable characteristics to drugs by modulating both the pharmacokinetics and pharmacodynamic properties of a drug. Therefore, incorporation of fluorine into a drug increases the lipophilicty enhancing absorption into biological membranes whereby its small covalent radius can facilitate docking with their drug receptor(s). By emphasising those structural features that modulate the absorption and metabolism of these compounds, when possible, structure-function relationships are discussed. Drug types are classified according to their therapeutic indication and utility rather than structural type and include phospodiesterase inhibitors, antiparasitic agents (especially antimalarials), anticancer compounds (such as kinases), antibacterials, and selected probes useful for 18 F positron emission tomography. #
The role of fluorine in medicinal chemistry
Journal of Enzyme Inhibition and Medicinal Chemistry, 2007
The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.
Applications of Fluorine in Medicinal Chemistry
The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pK a , intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18 F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
Fluorine important element in new drugs synthesis: Review Study
Iraqi Journal of Pharmacy, 2018
Objective:To evaluate the role of fluorine atom in modern drug synthesis. Methods: Different types of fluorinated were prepared, antimicrobials, antivirals, F-NSAIDs, peptides and protein synthesis. Results: Recent developments and future prospects of fluorine in medicinal chemistry and chemical biology. The extraordinary potential of fluorine-containing biologically relevant molecules in antimicrobial or antivirial agents, or peptide or protein chemistry, medicinal chemistry, chemical biology, pharmacology, and drug discovery as well as diagnostic and therapeutic applications, was recognized by researchers who are not in the traditional fluorine chemistry field, and thus the new wave of fluorine chemistry has been rapidly expanding its biomedical frontiers. Conclusion: This review how to list of fluorinated drugs(Antimicrobial agents , anticancer agents, Antiviral agents, and study their physicochemical properties of fluorine drugs.
Recent progress in the strategic incorporation of fluorine into medicinally active compounds
Journal of Fluorine Chemistry, 2018
This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to (i) taxoid anticancer agents, (ii) acylhydrazone-based antifungal agents and (iii) inhibitors of matrix metalloproteinase 9 (MMP9) for medicinal chemistry and chemical biology studies. In the case study (i), a series of next-generation fluorotaxoids, bearing m-OCF 3 or m-OCF 2 H group in the C2-benzoate moiety was designed, synthesized and examined for their potencies. A number of these fluorotaxoids possess two orders of magnitude greater potency in different drugresistant cancer cell lines as compared to paclitaxel. One of these next-generation fluorotaxoids, SB−−121205wasselected for detailed mechanistic study against highly paclitaxel-resistant human breast cancer cell line, MCF-7/PTX, which disclosed a unique mechanism of action. Recently, glucosylceramide (GlcCer) synthesis emerged as a promising target for next-generation antifungal agents, especially against cryptococcosis, candidiasis and pulmonary aspergillosis. The HTP screening of compound libraries identified several acylhydrazones as hit compounds. In the case study (ii), fluoro-acylhydrazones containing F, OCF 3 , OCHF 2 , o-F/p-OCF 3 , as well as o-F/p-CF 3 functional groups in the ring A and ring B were designed based on these hit compounds, synthesized and examined for their potencies against C. neoformans. A number of those novel fluoro-acylhydrazones exhibited high potency and excellent killing properties.
Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs
Journal of Medicinal Chemistry, 2020
Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic logP values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one
Journal of Fluorine Chemistry, 2008
On the one hand, owing to its electronegativity, relatively small size, and notable leaving group ability from anionic intermediates, fluorine offers unique opportunities for mechanism-based enzyme inhibitor design. On the other, the "bio-orthogonal" and NMR-active 19-fluorine nucleus allows the bioorganic chemist to follow the mechanistic fate of fluorinated substrate analogues or inhibitors as they are enzymatically processed. This article takes an overview of the field, highlighting key developments along these lines. It begins by highlighting new screening methodologies for drug discovery that involve appropriate tagging of either substrate or the target protein itself with 19 Fmarkers, that then report back on turnover and binding, respectively, via an the NMR screen. Taking this one step further, substrate-tagging with fluorine can be done is such a manner as to provide stereochemical information on enzyme mechanism. For example, substitution of one of the terminal hydrogens in phosphoenolpyruvate, provides insight into the, otherwise latent, facial selectivity of C-C bond formation in KDO synthase. Perhaps, most importantly, from the point of view of this discussion, appropriately tailored fluorinated functionality can be used to form to stabilized "transition state analogue" complexes with a target enzymes. Thus, 5-fluorinated pyrimidines, αfluorinated ketones, and 2-fluoro-2-deoxysugars each lead to covalent adduction of catalytic active site residues in thymidylate synthase, serine protease and glycosidase enzymes, respectively. In all such cases, 19 F NMR allows the bioorganic chemist to spectrally follow "transition state analogue" formation. Finally, the use of specific fluorinated functionality to engineer "suicide substrates" is highlighted in a discussion of the development of the α-(2′Z-fluoro)vinyl trigger for amino acid decarboxylase inactivation. Here 19 F NMR allows the bioorganic chemist to glean useful partition ratio data directly out of the NMR tube.
Late stage fluorination: lessons to be learned from the fluorinase enzyme
2019
The impact of fluorine chemistry in the life sciences is enormous. As many as 30−40% of agrochemicals and 20% of pharmaceuticals on the market are estimated to contain fluorine. 19 F-and 18 F-labelled compounds are also finding increasing applications in imaging such as Magnetic Resonance Imaging [MRI] or Positron Emission Tomography [PET]. As a result, there is an increasing demand for facile methods allowing for the fluorination using 19 F and the radioisotope 18 F of a large variety of structurally complex and functionalised small molecules as well as biologics. This lecture will discuss our recent contributions to the field of late stage fluorination with an emphasis on the challenges associated with the use of alkali metal fluoride, and how these can be overcome. The fluorinase enzyme will serve as a starting point for discussion.