Melatonin pharmacophoric motifs in the anancomeric spiranic oxindole-cycloalkane scaffold: Theoretical and 1H NMR conformational analysis

Martha S. Morales-Ríos, Daphne E. González-Juárez, Gelacio Martínez-Gudiño, Nury Pérez-Hernández, Luz María Del Razo, Humberto L. Mendoza-Figueroa, J. Benjamín García-Vázquez

Research output: Contribution to journalArticle

Abstract

N-[2′-oxospiro(cycloalkane-1,3′-indoline)methyl]acetamides (1a/b-4a/b), analogues conformationally restricted of neurohormone melatonin (MLT), were constructed through pharmacophoric ethylacetamido side chain incorporation into a chiral spiro-ring structure. A facile synthetic route was established to afford the epimeric spirocycloalkane pairs a/b starting from substituted spirocycloalkane nitriles through catalytic hydrogenation in acetic anhydride medium. The conformational profiles of the methylamido side chain were explored by computational methods. The main conformational features represent a balance between geometric restrictions imposed by the spiro-ring structure and the relative configuration of the corresponding stereocenters. The anancomeric structure of the spiranic oxindole-cycloalkane scaffold and the orientation of the amido side chain is discussed considering complete 750 MHz 1H NMR data by applying an iterative full spin analysis (HiFSA), conformational analysis, and single crystal X-ray diffraction. The effect of the conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed in terms of pharmacophore-based virtual screening.

Original languageEnglish
Article number127267
JournalJournal of Molecular Structure
Volume1202
DOIs
StatePublished - 15 Feb 2020

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Cycloparaffins
Melatonin
Scaffolds
Acetamides
Nuclear magnetic resonance
Nitriles
Stereochemistry
Computational methods
Hydrogenation
Neurotransmitter Agents
Screening
Single crystals
X ray diffraction
oxindole

Keywords

  • Bis-amides
  • Conformational restriction
  • Iterative H NMR analysis (HiFSA)
  • Melatonin
  • MEXOQPBTEIZEDZ-CXAGYDPISA-N
  • MEXOQPBTEIZEDZ-SUMWQHHRSA-N
  • Pharmacophore modelling
  • Spirooxindoles
  • WXQYDEGDTVANTI-BLLLJJGKSA-N
  • WXQYDEGDTVANTI-MLGOLLRUSA-N

Cite this

Morales-Ríos, Martha S. ; González-Juárez, Daphne E. ; Martínez-Gudiño, Gelacio ; Pérez-Hernández, Nury ; Del Razo, Luz María ; Mendoza-Figueroa, Humberto L. ; García-Vázquez, J. Benjamín. / Melatonin pharmacophoric motifs in the anancomeric spiranic oxindole-cycloalkane scaffold: Theoretical and 1H NMR conformational analysis. In: Journal of Molecular Structure. 2020 ; Vol. 1202.
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abstract = "N-[2′-oxospiro(cycloalkane-1,3′-indoline)methyl]acetamides (1a/b-4a/b), analogues conformationally restricted of neurohormone melatonin (MLT), were constructed through pharmacophoric ethylacetamido side chain incorporation into a chiral spiro-ring structure. A facile synthetic route was established to afford the epimeric spirocycloalkane pairs a/b starting from substituted spirocycloalkane nitriles through catalytic hydrogenation in acetic anhydride medium. The conformational profiles of the methylamido side chain were explored by computational methods. The main conformational features represent a balance between geometric restrictions imposed by the spiro-ring structure and the relative configuration of the corresponding stereocenters. The anancomeric structure of the spiranic oxindole-cycloalkane scaffold and the orientation of the amido side chain is discussed considering complete 750 MHz 1H NMR data by applying an iterative full spin analysis (HiFSA), conformational analysis, and single crystal X-ray diffraction. The effect of the conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed in terms of pharmacophore-based virtual screening.",
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author = "Morales-R{\'i}os, {Martha S.} and Gonz{\'a}lez-Ju{\'a}rez, {Daphne E.} and Gelacio Mart{\'i}nez-Gudi{\~n}o and Nury P{\'e}rez-Hern{\'a}ndez and {Del Razo}, {Luz Mar{\'i}a} and Mendoza-Figueroa, {Humberto L.} and Garc{\'i}a-V{\'a}zquez, {J. Benjam{\'i}n}",
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Melatonin pharmacophoric motifs in the anancomeric spiranic oxindole-cycloalkane scaffold: Theoretical and 1H NMR conformational analysis. / Morales-Ríos, Martha S.; González-Juárez, Daphne E.; Martínez-Gudiño, Gelacio; Pérez-Hernández, Nury; Del Razo, Luz María; Mendoza-Figueroa, Humberto L.; García-Vázquez, J. Benjamín.

In: Journal of Molecular Structure, Vol. 1202, 127267, 15.02.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Melatonin pharmacophoric motifs in the anancomeric spiranic oxindole-cycloalkane scaffold: Theoretical and 1H NMR conformational analysis

AU - Morales-Ríos, Martha S.

AU - González-Juárez, Daphne E.

AU - Martínez-Gudiño, Gelacio

AU - Pérez-Hernández, Nury

AU - Del Razo, Luz María

AU - Mendoza-Figueroa, Humberto L.

AU - García-Vázquez, J. Benjamín

PY - 2020/2/15

Y1 - 2020/2/15

N2 - N-[2′-oxospiro(cycloalkane-1,3′-indoline)methyl]acetamides (1a/b-4a/b), analogues conformationally restricted of neurohormone melatonin (MLT), were constructed through pharmacophoric ethylacetamido side chain incorporation into a chiral spiro-ring structure. A facile synthetic route was established to afford the epimeric spirocycloalkane pairs a/b starting from substituted spirocycloalkane nitriles through catalytic hydrogenation in acetic anhydride medium. The conformational profiles of the methylamido side chain were explored by computational methods. The main conformational features represent a balance between geometric restrictions imposed by the spiro-ring structure and the relative configuration of the corresponding stereocenters. The anancomeric structure of the spiranic oxindole-cycloalkane scaffold and the orientation of the amido side chain is discussed considering complete 750 MHz 1H NMR data by applying an iterative full spin analysis (HiFSA), conformational analysis, and single crystal X-ray diffraction. The effect of the conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed in terms of pharmacophore-based virtual screening.

AB - N-[2′-oxospiro(cycloalkane-1,3′-indoline)methyl]acetamides (1a/b-4a/b), analogues conformationally restricted of neurohormone melatonin (MLT), were constructed through pharmacophoric ethylacetamido side chain incorporation into a chiral spiro-ring structure. A facile synthetic route was established to afford the epimeric spirocycloalkane pairs a/b starting from substituted spirocycloalkane nitriles through catalytic hydrogenation in acetic anhydride medium. The conformational profiles of the methylamido side chain were explored by computational methods. The main conformational features represent a balance between geometric restrictions imposed by the spiro-ring structure and the relative configuration of the corresponding stereocenters. The anancomeric structure of the spiranic oxindole-cycloalkane scaffold and the orientation of the amido side chain is discussed considering complete 750 MHz 1H NMR data by applying an iterative full spin analysis (HiFSA), conformational analysis, and single crystal X-ray diffraction. The effect of the conformational restriction, ring size, and stereochemistry on melatoninergic agonist activity was analyzed in terms of pharmacophore-based virtual screening.

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KW - Conformational restriction

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KW - Melatonin

KW - MEXOQPBTEIZEDZ-CXAGYDPISA-N

KW - MEXOQPBTEIZEDZ-SUMWQHHRSA-N

KW - Pharmacophore modelling

KW - Spirooxindoles

KW - WXQYDEGDTVANTI-BLLLJJGKSA-N

KW - WXQYDEGDTVANTI-MLGOLLRUSA-N

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U2 - 10.1016/j.molstruc.2019.127267

DO - 10.1016/j.molstruc.2019.127267

M3 - Artículo

AN - SCOPUS:85075341659

VL - 1202

JO - Journal of Molecular Structure

JF - Journal of Molecular Structure

SN - 0022-2860

M1 - 127267

ER -