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.