Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group

Logvinenko, Ivan G.; Markushyna, Yevheniia; Kondratov, Ivan S.; Vashchenko, Bohdan V.; Kliachyna, Maria; Tokaryeva, Yuliya; Pivnytska, Valentyna O.; Grygorenko, Oleksandr O.; Haufe, Günter

doi:10.1016/j.jfluchem.2020.109461

Cited by 11 publications

(17 citation statements)

References 55 publications

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“…The deviated position in Figure 3 b for 2k (R 2 = 4-OCF 3 ) is probably caused by the specific characteristics of this moiety, e.g., [ 48 , 49 , 50 , 51 ], are therein similar to the unpredictable behavior of methoxy-substituted compounds observed in other studies, e.g., [ 45 , 52 , 53 , 54 , 55 ]. The last Figure 3 c shows the dependence of the surface tension on the activity.…”

Section: Resultssupporting

confidence: 56%

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Strhársky

Pindjakova

Kos

et al. 2022

IJMS

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A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.

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Section: Resultssupporting

confidence: 56%

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Strhársky

Pindjakova

Kos

et al. 2022

IJMS

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“…During compound optimization, the substitution of alkoxy groups with fluorinated homologues (e.g., OCH 3 to OCF 3 or OCHF 2 ) is an approach that has been used to modify both physicochemical properties and metabolite profile. , As substituents, OCF 3 groups usually confer enhanced lipophilicity compared with OCH 3 . This effect reflects both the higher intrinsic lipophilicity of fluorine (π = 0.14) and the inductive electron-withdrawing effects of fluorine that reduce the hydrogen-bond-accepting (p K HBX ) character of the oxygen atom. − However, exceptions to this trend have been noted, many of which involve a close proximal relationship between a fluorine substituent and an oxygen-containing functionality that is believed to impart increased overall polarity to a molecule, thereby favoring solvation in polar media . Increased lipophilicity is evident in higher measured log D values, but counterintuitively, this substitution may actually detract from passive permeability.…”

Section: Fluorinated Ethersmentioning

confidence: 99%

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C–F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

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“…[20,[27][28][29] It is widely recognized that introducing fluorinated substituents into potential biologically active compounds can finetune their physico-chemical parameters, improve metabolic stability, and provide additional opportunities for interactions with a biological target. [30][31][32][33] The literature search reveals that a few fluorinated 2-heterabicyclo[2.1.1]hexane derivatives have been described previously (Figure 1B). In particular, 4-fluoroand 4-fluoromethyl-2,4-methanoprolines 1 and 2 were synthesized by our group [34] and Cox and co-workers, [20] respectively.…”

Section: Introductionmentioning

confidence: 99%

4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

et al. 2021

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A gram-scale synthesis, physico-chemical characterization, and lead-likeness assessment of 4-di/trifluoromethyl-2-heterabicyclo [2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3-hydroxy-/3aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4-di/ trifluoromethyl-2,4-methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane-derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2-oxabicyclo[2.1.1]hexanes, pK a and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, finetuned lipophilicity intermediate between that of non-fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead-like chemical space, had higher three-dimensionality, and showed lower mean lead-likeness penalty as compared to those obtained from either non-fluorinated or aromatic derivatives.

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Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group

Cited by 11 publications

References 55 publications

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

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