Synthetic Strategies for the Construction of δ-Carbolines: A Chemical Ladder in Search of Novel Drugs

Abstract

Carboline and its naturally obtained analogs are of importance due to their wide range of biological properties. In the present review, we intend to discuss the main trends in the synthesis of-carboline analogs based on pyridine derivatives (including the Fischer synthesis, Graebe-Ullmann reaction, photochemical cyclization, arylation of substituted pyridines, quinolines, etc.) and indole derivatives in order to compare the potential of finding novel drugs in this series. In other words the development, current status and innovative new options for the design and synthesis of-carboline analogs are reviewed here. Published data about the various pharmacological functions and the spectroscopy of compounds belonging to this series are summarized. It also discusses the scope, future perspectives and the problems yet to be explored with respect to the synthesis of functionalised bioactive heteroannulated-carbolines in search of novel drugs.

Anti‐Tubercular Insights of Carbolines – A Decade Critique

“…Cryptoleptine and benzo-carboline synthetic salt shown in Figure 7 are the δderivative with significant biological activities. [44] Spath and Eiter reported the Synthesis of δ-carboline derivatives [45] by Graebe-Ullmann reaction using o-phenylenediamine (50) and 3-bromopyridine (51) in the presence of copper sulfate at 155°C for 9 h results in the formation of N1-(pyridine-3-yl)-benzene-1,2-diamine, (52) which gets transformed into 1-(pyridin-3-yl)-1H-benzo-…”

“…Only after the initial Synthesis by Bremer in 1934, γcarbolines (5H-pyrido [4,3-b]indole) came to attention. [18] Two bioactive γ-carbolines: Latrepirdine (43) and gevotroline (44), are depicted in Figure 6. This moiety has also shown inhibition against bromodomain and extra terminal proteins (BET), DNA intercalators, and potential anti-Alzheimer agents.…”

“…[18,20] 4.5. δ-carbolines δ-carbolines (5H-pyrido-[3,2-b]-indoles) are the least studied class of compounds compared to other isomeric forms of carbolines. [44] Although no effective drugs have been found among δ-carbolines but a broad spectrum of biological activities [45] like anti-muscarinic, [46] anti-hyperglycemic, [47] antimalarial, [48] anti-plasmodial, [49] anti-fungal, [50] anticryptococcal, [51] anti-viral, [52] and anti-tumor activity [44] have been reported among this class of carboline. Cryptoleptine and benzo-carboline synthetic salt shown in Figure 7 are the δderivative with significant biological activities.…”

Synthesis and Optical Properties of Alkaloid Quindoline, Its Structural Analogues and Substituted δ‐Carbolines

“…The methods for the synthesis of quindoline and its structural analogues are based mainly on the annelation of the indole ring to quinoline or the quinoline ring to indole ,. One of 15 methods for the synthesis of quindoline includes the reductive Cadogan cyclization of 2‐(2‐nitrophenyl)quinoline with triethyl phosphite at the final stage …”

“…Currently, there is no single general method by which to synthesize the δ‐carbolines. The classical Fischer and Graebe–Ullmann reactions have been used for single examples of the synthesis of only unsubstituted δ‐carbolines, which is due to the inaccessibility of other starting materials for these reactions . A majority of substituted δ‐carbolines has been synthesized using six reactions such as the Rh II 2 ‐catalyzed thermolysis reaction of 1‐methyl‐2‐(2‐azidoaryl)pyridinium triflate obtained by Suzuki cross coupling‐azidation‐methylation scheme; the arylation of 3‐aminopyridines (Buchwald–Hartwig reaction) and subsequent intramolecular closure of the pyrrole ring using palladium acetate to form a C–C bond; the intramolecular reaction of nucleophilic substitution of the fluorine atom in the position 3 of the pyridine core with the o ‐amino and pivaloylamino group of the phenyl substituent; the Pd‐catalyzed reaction of 2‐iodoanilines with N ‐tosylenynamines and the Ni‐catalyzed [2+2+2] cycloaddition of internal alkynes to o ‐ N ‐(tosyl)alkynylbenzonitriles; the three‐component reaction of 1‐acetylindolin‐3‐ones, β,γ‐unsaturated α‐ketoesters and amines under aerobic conditions; the reductive Cadogan cyclization of 2‐aryl‐3‐nitropyridines obtained by the five steps from a minor product in the nitration of 2‐aminopyridine …”