Diversity-Oriented Synthesis of Spiropyrrolo[1,2-a]isoquinoline Derivatives via Diastereoselective and Regiodivergent Three-Component 1,3-Dipolar Cycloaddition Reactions: In Vitro and in Vivo Evaluation of the Antidiabetic Activity of Rhodanine Analogues

Abstract

An efficient diastereoselective route is developed to get access to novel spiropyrrolo­[1,2-a]­isoquinoline-oxindole skeletons by a one-pot three-component [3 + 2] cycloaddition reaction of (Z)-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydro­isoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo-dispiro­pyrrolo­[2,1-a]­isoquinoline­oxindoles in excellent yield. Unprecedentedly, each isomeric dispiro­pyrrolo­[2,1-a]­isoquinoline­oxindole endured retro-1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g­(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo-stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with (Z)-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine analogues were formed, along with smaller amounts of a dispirooxindole-piperazine. The structure and the relative configuration of these N-heterocycles were unambiguously assigned by spectroscopic techniques and confirmed by four single-crystal structures. In vitro and in vivo studies reveal that the novel rhodanine derivatives exert antidiabetic activity. The binding affinity with the active site of the enzyme α-amylase was studied by molecular docking. Furthermore, the bioavailability assessed through virtual ADME parameters (Absorption, Distribution, Metabolism, Elimination pharmacokinetics) and the excellent fit with the Lipinski and Veber rules predict good drug-likeness properties for a bromo-substituted 2-sulfanylidene-1,3-thiazolidin-4-one.

Stereoselective Synthesis of Dispirooxindoles Incorporating Pyrrolo[2,1-a]isoquinoline via [3+2] Cycloaddition of Azomethine Ylides with a Thiazolo[3,2-a]indole Dipolarophile

“…On account of our continued interest in the chemistry of thieno[2,3- b ]indole-2,3-dione 23 and thiazolo[3,2- a ]indole derivative, 21 we made detailed investigations regarding [3+2] cycloaddition of 3a with azomethine ylide derived from isatins and 1,2,3,4-tetrahydroisoquinoline, which led to the synthesis of dispirooxindoles containing pyrrolo[2,1- a ]isoquinolines. Previous reports 24 25 26 on the direct synthesis of pyrrolo[2,1- a ]isoquinolines reveal that the regioselectivity of the reaction depends on the nature of the dipolarophile used as seen from Scheme 2 .…”

The Bioactivity of Thiazolidin-4-Ones: A Short Review of the Most Recent Studies

“…The most active in vitro Compound 88d from Series 2 (IC 50 = 5.98 µM) was tested with alloxan-induced diabetic rats on intestinal α-amylase activity and the blood glucose level. The administration of Compound 88d at dose of 30 mg/kg daily for 21 days significantly reduced the intestinal α-amylase activity by 21.3% in comparison with untreated diabetic rats, decreased the blood glucose level by 39% [89].…”

“…the blood glucose level. The administration of Compound 88d at dose of 30 mg/kg daily for 21 days significantly reduced the intestinal α-amylase activity by 21.3% in comparison with untreated diabetic rats, decreased the blood glucose level by 39% [89].…”

“…Toumi et al [88,89] carried out assay of series of rhodanine derivatives for their αamylase inhibitory activity. The first series rhodanine-based spirooxindole pyrrolidine derivatives (86a-86o and 87a-87d) (Figure 36) showed promising activities toward α-amylase enzyme.…”

Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds

“…In continuation of our research interests in the synthesis of novel bioactive N-spirohete -rocycles [5,[54][55][56][57], we herein report the synthesis of diverse thiochromanone/chromanone substituted spiropyrrolidines (Figure 1). The latter were obtained via multicomponent reactions (MCRs) of arylidene thiochroman-4-ones/chroman-4-ones, glycine ethyl ester, and cyclic 1,2-diketones (isatin derivatives or acenaphthenequinone) (Scheme 1).…”