Martha S. Morales-Ríos

Synthesis and biological evaluation of (-)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors.

A series of pyrrolidinoindolines have been synthesized as debromoflustramine B (4a) analogues for their evaluation as cholinesterase inhibitors. Structure-activity studies of this series revealed the optimum pharmacophoric elements required for activity and resulted in the discovery of selective butyrylcholinesterase inhibitors with micromolar potency. Biological testing demonstrated that (-)-4a was 7500 times more potent than its enantiomer (+)-4b. The most active inhibitor against BChE in the series was demethyldebromoflustramine B (5a), with an IC50 value of 0.26 microM. X-ray crystallography of 15 and docking studies of selected compounds into human BChE (PDB 1POI) are presented. Molecular modeling studies showed that pi-hydrogen bond, classical hydrogen bond, and cation-pi interactions are critical for optimum potency.

Trans-3-Phenyl-2-Propenoic Acid (Cinnamic Acid) Derivatives: Structure-Activity Relationship as Hepatoprotective Agents

Among various phenolic compounds, caffeic acid (3,4-dihydroxycinnamic acid) exhibited pharmacological antioxidant, anticancer and antimutagenic activities. The antioxidant properties of phenolic compounds depend on their chemical structure, however, the role of the ethylenic side chain in the radical scavenging activity remains controversial. Thus, the aim of this study consisted to test cinnamic acid and 15 cinnamic acid derivatives in the well known CCl(4)-induced acute liver damage model, which is dependent on oxidative stress mechanisms. Cinnamic acid and 15 cinnamic acid derivatives (50 mg/kg, p.o.) were administered to male Wistar rats intoxicated with CCl(4) (4 g/kg, p.o.). The activities of gamma-glutamyl transpeptidase, alkaline phosphatase and alanine aminotransferase were measured in serum. The lipid peroxidation products were determined in liver. Compounds with a methoxy group at position 3 or 4, or a 3,4-methylenedioxy moiety were the most active ones. Also, we observed that the monosubstituted 3 or 4 hydroxy, or the bulky 3,4 dibenzyloxy substituted compounds showed lower activity. The poorest activity was displayed by disubstituted 3,4-dihydroxy, dimethoxy or diacetyl cinnamic acid derivatives, the ester derived from cinnamic acid with an 8 carbon chain and N-dimethyl substituted compound. Thus, the methoxy substituted group at positions 3 or 4 or the 3,4-methylenedioxy moiety in the caffeic acid derivatives; seem to be the main features required for the hepatoprotection in this model.

First total syntheses of dihydroflustramine C and flustramine E, alkaloids from the marine bryozoan Flustra foliacea

Abstract We have developed a simple and practical method for providing the common tricyclic skeleton of physostigmine type alkaloids, and demonstrated its utility for indole alkaloid synthesis. Thus, we achieved the first total syntheses of (±)-dihydroflustramine C and (±)-flustramine E, as well as the total syntheses of their debromoanalogues from the corresponding 2-hydroxyindolenines in five steps with 31, 27, 39 and 23% overall yields, respectively. The structures of some intermediates were confirmed by single crystal X-ray diffraction analyses.

AN EFFICIENT APPROACH TO 1,3,5-TRIS-ARYLHEXAHYDRO-1,3,5-TRIAZINES

ABSTRACT In this paper we report a facile and efficient procedure for the synthesis of 1,3,5-tris-arylhexahydro-1,3,5-triazines (3) by reaction of anilines 1 with 1,3,6,8-tetrazatricyclo[4.4.1.1[3], [8a], [8b]- dodecane (TATD) (2). The diequatorial chair conformational preference of 3b (Ar = p-tolyl) in the solid state was established by X-ray crystallography and agrees well with molecular mechanics calculations.

Push–pull and pull–push effects in isatylidenes

A series of C‐8 mono‐ and disubstituted isatylidenes were prepared in order to examine the influence of the substituent on the polarization of the ethylenic carbons C‐3=C‐8. Donor–acceptor C‐8 substitution resulted in an inversion of the polarization of the ethylenic carbons, as evidenced by the 13C NMR spectra, and because these compounds can exist in solution as equilibrium mixtures of the E‐ and Z‐isomers. The dual donor–acceptor character of the heterocycle is controlled by the cross‐conjugated C‐3=C‐8 double bond, in which the C‐3 carbon atom has the possibility of conjugating with either the donor or the attracting portion of the heterocyclic system, consistent with contributions from isatylidene resonance forms which induce the C‐8 carbon atom to be charged either positively or negatively, thus allowing an opposite sense of the push–pull effect. Copyright

FORMAL SYNTHESIS OF ()-PHYSOSTIGMINE

Abstract The formal synthesis of the indole alkaloid (±)-physostigmine (1) from (Z)-2-hydroxy-5-methoxyindolenine9 is described. The key step of the synthesis is a novel diasteroselective conjugated addition of a Grignard reagent to 9. The relative stereochemistry of the newly formed contiguous chiral centers is established by X-ray crystallography. The stereocontrolled conjugated addition involves the directing effect of the neighboring hydroxyl group to afford 12. Oxidation of 12 with CrO 3 AcOH leads to oxindole 14. Decarboxylation of the latter, followed by N-methylation gave 2,3-dihydro-5-methoxy-1,3-dimethyl-2-oxo-1H-indole-3-acetonitrile (3), a known precursor for physostigmine (1).

Nouvelle voie d'accès au squelette de la (±)-physostigmine

Abstract Grignard 1,4-addition of methyl magnesium iodide to 2-hydroxyindolenine 3, followed by oxydation with CrO3/AcOH, led diastereoselectively to methyl 2-cyano-2-(1-carbomethoxy-3-methyl-2-oxo-3-indolyl)acetate 5. Decarboxylation of 5 and thence N-methylation gave 3-acetonitril-3-methylindol-2-one, 2, which is an intermediate in the synthesis of the (±)-physostigmine 1 framework.

Synthese directe d'indoles anti-hypertensifs

Abstract The direct syntheses of two potencial anti-hypertensive drug candidates having the indole skeleton ( 2 and 3 ), using the β-cyanoaldehyde 6 or a γ-amide-aldehyde in Fischer condesations with ϱ-methoxyphenylhydrazine are described. As by-products from these syntheses we isolated the chloropyrrole ( 11 ) and two diasteroisomeric molecules ( 12 -E and 12 -Z), one of them leading selectivity to the N-acetylpyrrole 13 . The structure and stereochemistry of three of these minor products ( 10 , 12 -E and 14 ) were confirmed by single crystal X-ray diffraction studies.

NMR studies of 4(3H)-quinazolinones and 4(3H)-quinazolinethiones

SummaryUnambiguous1H and13C NMR assignments for 4(3H)-quinazolinones1–6 and their corresponding 4-thiones7–12 have been made. This resulted in the revision of the previous assignments for the two benzenoid carbons (C-5 and C-8) of quinazolinones1,2,4, and5. Thionation of the nucleophilic amides1–6 has been found to cause a distinct change in the13C chemical shift of particularly C-4, but also of those of C-4a, C-5, and C-8a. One-bond and several long range heteronuclear coupling constants for the compounds have also been measured.ZusammenfassungDie1H- und13C-NMR-Spektren der 4(3H)-Chinazolinone1–6 und ihrer entsprechenden 4-Thione7–12 wurden zugeordnet. Dabei zeigte sich, daß eine frühere Zuordnung der beiden benzoiden Kohlenstoffe (C-5 und C-8) der Chinazolinone1,2,4 und5 falsch war. Ersatz des Sauerstoffs durch Schwefel in den nukleophilen Amiden1–6 führt insbesondere für C-4, aber auch für C-4a, C-5 und C-8a zu einer deutlichen Änderung der chemischen Verschiebung. Heteronukleare Kopplungskonstanten über eine und über mehrere Bindungen wurden bestimmt.

A convenient preparation of furo[2,3-b]indoles by conjugated addition of organomagnesium reagents to 2-hydroxyindolylidenemalonates

The chelate-controlled conjugated addition of Grignard reagents to 2-hydroxyindolylidenemalonates was studied as a means of preparing 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles in one or two steps. In addition to the alkylorganometallic group variation, the effects of substitution at the aromatic ring on the reaction outcome were established. The indolylidenemalonates were found to be less reactive than the analogous indolylidenecyanoacetates.