Pyrrolo[2,1- a ]isoquinoline Scaffold in Drug Discovery: Advances in Synthesis and Medicinal Chemistry

Abstract

Pyrrolo[2,1- a]isoquinoline (PIq) is a nitrogen heterocyclic scaffold of diverse alkaloids endowed with several biological activities, including antiretroviral and antitumor activities. Several 5,6-dihydro-PIq (DHPIq) alkaloids, belonging to the lamellarins’ family, have proved to be cytotoxic to tumor cells, as well as reversers of multidrug resistance. In this review, we provide an overview of the main achievements over the last decade in the synthetic approaches to access libraries of PIq compounds along with a survey, as comprehensive as possible, of bioactivity, mechanism of action, pharmacophore and structure–activity relationships of synthetic analogs of DHPIq-based alkaloids. The focus is mainly on the potential exploitation of the (DH)PIq scaffold in design and development of novel antitumor drugs.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives

“…Particularly, fused compounds containing quinoline and isoquinoline moieties constitute select classes of compounds, both heterocycles being widely explored for the development of bioactive molecules [3,5,6]. Notably, pyrrolo [2,1-a]isoquinoline is a common scaffold in multiple alkaloids (crispines, trolline, lamellarins) having diverse biological action, including antitumor, antibacterial, antifungal and antiviral activities [7][8][9].…”

“…Considering the biological relevance of these two important scaffolds and the positive tendency for their further development, pyrrolo(iso)quinoline derivatives have increasingly become targets of interest in the organic synthetic community. Over the past decades, several synthetic methodologies to generate compounds with pyrrolo[2,1-a]isoquinoline or pyrrolo [1,2-a]quinoline cores have been developed, including the [3 + 2] cycloaddition of the corresponding cycloimmonium ylides to various dipolarophiles, cyclization of lactam derivatives, intramolecular cyclizations, as well as several transition metal catalyzed C-C and C-N bond formation reactions [3,6,16]. It is worth mentioning that the nature and the position of the substituents in the core-containing compounds define their biological profile.…”

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

“…driven the development of various approaches for its obtaining -based either on isolation from naturally occurring sources or through multistep synthetic routes [6]. The pyrrolo[2,1-a]isoquinoline skeleton is incorporated in a large group of natural compounds such as crispines, trolline, and lamellarins, which are interesting due to their anticancer, antiviral, and antibacterial activities [7,8]. In the light of this broad array of biological activities, the development of novel methods for the construction of these heteropolycycles is of great significance to both organic and medicinal chemistry.…”

“…The Castagnoli-Cushman reaction (CCR) between cyclic enolizable anhydrides (such as succinic (5) [9], glutaric (6) [10], and the corresponding oxygen (7) [11], sulfur (8) [11], and nitrogen analogs 9 [12], and homophthalic anhydride (10) [13,14]) and imines 11, 12 offers a route to substituted lactam molecules 13 and 14 [13][14][15][16][17][18][19]. Among them, the reactions of homophthalic anhydride (10) with Schiff bases 11 or cyclic imines 12 have been examined in detail (Scheme 1) [13,14,20,21].…”

Green synthesis of pyrrolo isoquinolines using in situ synthesis of 4‐hydroxycumarines: Study of antioxidant activity

“…For these reasons, the synthesis of these compounds is very important and some important methods are reported in the literature. [ 14–17 ] Our procedure for the synthesis of pyrrolo[2,1‐ a ]isoquinoline is very simple and the catalyst used is natural and inexpensive. Moreover, separation of the product by our procedure is easy in comparison with the reported articles, and the yield and rate of reaction in my procedure are higher than a few articles reported.…”