The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Spirotetrahydro β-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.

The factors that control the relative and absolute stereochemistry of 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-β-carbolines formed via the Pictet–Spengler reaction are discussed. In particular, the stereochemical factors that lead to the predominance of cis-1,3-disubstituted products under conditions of kinetic control are presented, with the aid of X-ray crystallographic data on a number of compounds; methods for assigning relative stereochemistry on the basis of NMR data are given; the mechanism by which racemisation can occur during the Pictet–Spengler reaction has also been studied, and procedures for eliminating this problem are given.

Diastereo- and enantio-selectivity in the Pictet–Spengler reaction

β-Carboline derivatives display a wide range of interesting biological activities from
intercalation to enzyme inhibition and anticancer to psychological activity. β-
Carboline compounds are frequently isolated from natural products in the β-
carbolinium form and thus contain a bridgehead quaternary nitrogen.

Synthesis and reaction of novel nitrogen bridgehead heterocycles

(1R,3S)-2-Benzyl-3-methoxycarbonyl-1-methylcarboxymethyl-1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole, C23H24N2O4, was synthesized by a modified Pictet-Spengler reaction, and its crystal and molecular structure determined by single crystal X-ray diffraction methods. The crystals are monoclinic:P21 (No. 4),a=11.336(1),b=8.919(1),c=10.314(1)A,β=100.81(1)°,Z=2. The structure has been solved by direct methods, and refined toR=0.041 for 2203 observed reflections. The six-membered heterocyclic ring is in a half-chair conformation, and the substituents at C(3) and C(5) occupy axial and equatorial positions respectively. The CH2Ph group attached to N(4) is in the generally less favoured axial position. The nitrogen atom of the indole system forms an intermolecular hydrogen bond with the carbonyl oxygen of the CH2CO2 Me group, the N⋯O distance being 2.995(3)A.

Crystal and molecular structure of aN(2)-benzyl-1,3-disubstituted-1,2,3,4-tetrahydro-β-carboline

http://journals.iucr.org/c/issues/1989/11/00/an0223/an0223.pdf

C. D. Reynolds

Papers

Structure of dimethyl (1S,3S)‐1‐methoxycarbonylmethyl‐1,2,3,4‐tetrahydro‐9H‐pyrido[3,4‐b]indole‐1,3‐dicarboxylate at 165 K

Diastereo‐ and Enantioselectivity in the Pictet‐Spengler Reaction.

Asymmetric Route to the Demethoxy-fumitremorgins.