Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness

Berninger, Michael; Erk, Christine; Fuss, Antje; Skaf, Joseph; Al‐Momani, Ehab; Israel, Ina; Raschig, Martina; Güntzel, Paul; Samnick, Samuel; Holzgrabe, Ulrike

doi:10.1016/j.ejmech.2018.04.055

Cited by 9 publications

(3 citation statements)

References 36 publications

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“…30 The fluorine-and nitrogen-walk approaches, which respectively involve the replacement of a hydrogen atom with fluorine or a CH-function with nitrogen have been reported as successful approaches to optimize biological activity, metabolic stability, and overall physicochemical properties. [31][32][33][34] Here, we report the application of fluorine-and nitrogen-walk approaches to the GAT211 scaffold to develop potent and efficacious CB1R allosteric modulators with improved physicochemical properties. We detail the development of the resulting novel analogs and their in vitro characterization through functional assays (cAMP, β-arrestin2, GTPγS), including electrophysiological and radioligand binding experiments.…”

Section: Introductionmentioning

confidence: 99%

“…In general, SAR studies of GPCR allosteric modulators have been reported to be challenging, yielding a flat-SAR . The fluorine- and nitrogen-walk approaches, which, respectively, involve the replacement of a hydrogen atom with fluorine or a CH-function with nitrogen have been reported as successful approaches to optimize biological activity, metabolic stability, and overall physicochemical properties. − …”

Section: Introductionmentioning

confidence: 99%

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Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

et al. 2019

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Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro-and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, βarrestin2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

et al. 2019

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“…The assay was a validated screening of a kinase-focused library composed of 4000 compounds, leading to the discovery of novel scaffolds with potent antitrypanosomal activity [ 53 ]. In the recent years, thanks to different screening initiatives, several new leads such as diamidine derivatives, fexinidazole, oxaborole SCYX-7158, quinolone amide GHQ168, and acoziborole are now in various stages of the development pipeline for treating HAT [ 54 , 55 , 56 ].…”

Section: Trypanosomatids′ Life Cycle In the Context Of In Vitro Scmentioning

confidence: 99%

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Bhattacharya

Corbeil

Monte-Neto

et al. 2020

Genes

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Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds.

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Predicting ¹⁹F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

Dietschreit

Wagner

et al. 2020

Angewandte Chemie

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The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of 19F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.

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Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness

Cited by 9 publications

References 36 publications

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Predicting ¹⁹F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

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Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness

Cited by 9 publications

References 36 publications

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

Contact Info

Product

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Predicting ¹⁹F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex