The Methylation Effect in Medicinal Chemistry

Barreiro, Eliezer J.; Kümmerle, Arthur Eugen; Fraga, Carlos A.M.

doi:10.1021/cr200060g

Cited by 701 publications

(420 citation statements)

References 273 publications

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“…Interestingly, on closer inspection the effect of this group is not exactly what is classically termed the "magic methyl" effect (Leung et al, 2012), where the addition of a single methyl group in the "right" location on a scaffold results in a dramatic increase in activity, but rather a relatively modest 2.5-fold increase in potency on K Ca 3.1 combined with a moderate 3-5 loss in potency on K Ca 2.3 which overall results in a 40-100 fold increase in K Ca 3.1 selectivity compared with SKA-31. Given that these changes, although quite effective when combined, do not suggest major steric hindrance from stabilization of, for example, a large rotatable ring (Barreiro et al, 2011), we suspected that the gain in selectivity is primarily driven by hydrophobic interactions (e.g. the amount of hydrophobic protein surface buried upon ligand binding).…”

Section: Discussionmentioning

confidence: 99%

Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121)

et al. 2017

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Intermediate-conductance (K Ca 3.1) and small-conductance (K Ca 2) calcium-activated K + channels are gated by calcium binding to calmodulin (CaM) molecules associated with the calmodulin binding domain (CaM-BD) of these channels. The existing K Ca activators like SKA-31, NS309and EBIO activate both channel types with similar potencies. In a previous chemistry effort we optimizes the benzothiazole pharmacophore of SKA-31 towards K Ca 3.1 selectivity and identified SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which exhibits 40-fold selectivity for K Ca 3.1 over K Ca 2.3. In order to understand why introduction of a single CH 3 group in 5-position of the benzothiazole/oxazol system could achieve such a gain in selectivity for K Ca 3.1 over K Ca 2.3 we first localized the binding site of the benzothiazoles/oxazoles to the CaM-BD/CaM interface and then used the RosettaLigand computational modeling software to generate models of the K Ca 3.1 and K Ca 2.3 CaM-BD/CaM complexes with SKA-121. Based on a combination of mutagenesis and structural modeling we suggest that all benzothiazoles/oxazoles-type K Ca activators bind relatively "deep" in the CaM-BD/CaM interface and hydrogen-bond with E54 on CaM. In K Ca 3.1

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Section: Discussionmentioning

confidence: 99%

Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121)

et al. 2017

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“…However, NAH compound 1 does not structurally match the compounds described in previous reports. Perhaps an ortho steric effect, exerted by the methyl group on the carbonyl, and/or an electronic effect induced by the pyrimidine ring could be related to the observed phenomenon [28]. Thus, we decided to study the stereoelectronic requirements for the existence of conformers.…”

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confidence: 99%

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

et al. 2013

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Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1 H-and 13 C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1 H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the OPEN ACCESSMolecules 2013, 18 11684 electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the ΔG ≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond-related conformations.

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“…Observou-se que a inclusão de um grupo metila no carbono 5 do anel imidazol da histamina (22) levaria ao aumento da densidade eletrônica sobre o N-1 favorecendo, no equilíbrio, um dos tautômeros da 4-metil-histamina (23), o que ofereceu atributos para o desenho de um antagonista seletivo, a cimetidina (2). 23,24,26 (Esquema 5).…”

Section: Desenho Sob Medidaunclassified

“…4 Considerando a função N-acilidrazona (NAH) (24) (Figura 8), a denominação de estrutura privilegiada se deve ao extenso trabalho desenvolvido pelo LASSBio® através da exploração de abordagens da Química Medicinal no desenvolvimento de candidatos a fármacos, onde esse grupamento foi extensamente estudado e reunidos em algumas publicações quanto a suas diversas atividades biológicas. 26,30,31 Neste contexto, a subunidade NAH (24), como outras estruturas privilegiadas, podem consistir em uma vertente importante como ponto de partida para o desenho sob medida de fármacos. 13 …”

Section: 27unclassified

Medicinal Chemistry Approaches to Design of Drug Prototypes

Silva¹

2013

Revista Virtual De Química

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Abstract:The purpose of this paper is to present approaches of Medicinal Chemistry to drugs design in an objective way. In this case, it was considered the changes of paradigms and the acquisition of new technologies that have involved this scientific area throughout the time. Analog Design, Systematic Screening, Rational Drug Design and the Exploitation of Biologic Information were here presented by classic examples of literature concerning innovative drugs. These approaches could serve as examples to design new drug prototypes, in special for several diseases that currently have no appropriate treatment.

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The Methylation Effect in Medicinal Chemistry

Cited by 701 publications

References 273 publications

Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121)

Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121)

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

Medicinal Chemistry Approaches to Design of Drug Prototypes

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