In light of the significant correlation between inflammatory alterations andmetabolic dysfunction throughout different stages ofmetabolicdiseaseprogression, we focusedon utilizing our previously characterized glitazone-derived anti inflammatory 1,2,3-triazoles as lead compounds to create new multitargetdirectedligands that interactwithCOX-2,peroxisome proliferator-activated receptor γ (PPARγ), and CAwithin the framework of metabolic disorders. Notably, seven compounds exhibited equivalent or similar COX-2 inhibitory effects to celecoxib.Fourcompounds,namely,3b,3e,5e, and5h, exhibited substantialnanomolar inhibitoryeffectsagainsthCAI, II, IV, and IX isoforms (Ki 8.5−833, 0.37−24.6, 44.2−777, and27.3−32.1 nM, respectively). Furthermore, compounds 5e and5hdemon stratedasignificant increaseinglucoseuptakeintherathemidiaphragmexperiment,outperformingpioglitazone.ArobustPPARγ agonisminluciferaseassay, full-lengthhumanPPARγ transactivationwithout artificially increasing itsexpression, andisothermal titrationcalorimetry forKd determinationwereused to substantiate theirPPARγ-dependent insulin-sensitizing activity. Invivo pharmacokineticandtissuedistributionexperimentswerecarriedout, revealing favorableproperties.The invitroactivitieswere reflectedintoeffective invivoanti-inflammatorypotential intheformalin-inducedratpawedemaassay, andtheyalsoexhibiteda favorableulcerogenicprofile.Furthermore, computational targetpredictionandnetworkpharmacologyanalysis for thetwomost activemolecules,5eand5h, identifiedimportantbiologicalpathwaysassociatedwiththeintendedoutcomes. Inthisregard,5eand 5hnotonlymitigatedhyperglycemiaandinsulinresistanceinaninvivoratmodeloftype2diabetesbutalsoprotectedagainstrenal andlipemicdamagecausedbymetabolicdysfunction.Finally,dockingsimulationsindicatedpotentialbindinginteractionswiththe intendedbiological targets.
Elzahhar, P.A., Nematalla, H.A., Abouayana, M.A., El Ashry, E.S.H., Balbaa, M., Petreni, A., et al. (2025). Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction. ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, 8(6), 1627-1658 [10.1021/acsptsci.5c00011].
Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction
Spagnuolo, Rosaria;Naldi, Marina;Bartolini, Manuela;
2025
Abstract
In light of the significant correlation between inflammatory alterations andmetabolic dysfunction throughout different stages ofmetabolicdiseaseprogression, we focusedon utilizing our previously characterized glitazone-derived anti inflammatory 1,2,3-triazoles as lead compounds to create new multitargetdirectedligands that interactwithCOX-2,peroxisome proliferator-activated receptor γ (PPARγ), and CAwithin the framework of metabolic disorders. Notably, seven compounds exhibited equivalent or similar COX-2 inhibitory effects to celecoxib.Fourcompounds,namely,3b,3e,5e, and5h, exhibited substantialnanomolar inhibitoryeffectsagainsthCAI, II, IV, and IX isoforms (Ki 8.5−833, 0.37−24.6, 44.2−777, and27.3−32.1 nM, respectively). Furthermore, compounds 5e and5hdemon stratedasignificant increaseinglucoseuptakeintherathemidiaphragmexperiment,outperformingpioglitazone.ArobustPPARγ agonisminluciferaseassay, full-lengthhumanPPARγ transactivationwithout artificially increasing itsexpression, andisothermal titrationcalorimetry forKd determinationwereused to substantiate theirPPARγ-dependent insulin-sensitizing activity. Invivo pharmacokineticandtissuedistributionexperimentswerecarriedout, revealing favorableproperties.The invitroactivitieswere reflectedintoeffective invivoanti-inflammatorypotential intheformalin-inducedratpawedemaassay, andtheyalsoexhibiteda favorableulcerogenicprofile.Furthermore, computational targetpredictionandnetworkpharmacologyanalysis for thetwomost activemolecules,5eand5h, identifiedimportantbiologicalpathwaysassociatedwiththeintendedoutcomes. Inthisregard,5eand 5hnotonlymitigatedhyperglycemiaandinsulinresistanceinaninvivoratmodeloftype2diabetesbutalsoprotectedagainstrenal andlipemicdamagecausedbymetabolicdysfunction.Finally,dockingsimulationsindicatedpotentialbindinginteractionswiththe intendedbiological targets.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
