Abstract
Metformin, one of the most frequently prescribed oral anti-diabetic drugs, is characterized by multidirectional activity, including lipid lowering, cardio-protective and anti-inflammatory properties. This study presents synthesis and stability studies of 10 novel sulfonamide-based derivatives of metformin with alkyl substituents in the aromatic ring. The potential of the synthesized compounds as glucose-lowering agents and their effects on selected parameters of plasma and vascular hemostasis were examined. Compounds with two or three methyl groups in the aromatic ring (6, 7, 9, 10) significantly increased glucose uptake in human umbilical vein endothelial cells (HUVECs), e.g., 15.8 µmol/L for comp. 6 at 0.3 µmol/mL versus 11.4 ± 0.7 µmol/L for control. Basic coagulation studies showed that all examined compounds inhibit intrinsic coagulation pathway and the process of fibrin polymerization stronger than the parent drug, metformin, which give evidence of their greater anti-coagulant properties. Importantly, synthesized compounds decrease the activity of factor X, a first member of common coagulation pathway, while metformin does not affect coagulation factor X (FX) activity. A multiparametric clot formation and lysis test (CL-test) revealed that the examined compounds significantly prolong the onset of clot formation; however, they do not affect the overall potential of clot formation and fibrinolysis. Erythrotoxicity studies confirmed that none of the synthesized compounds exert an adverse effect on erythrocyte integrity, do not contribute to the massive hemolysis and do not interact strongly with the erythrocyte membrane. In summary, chemical modification of metformin scaffold into benzenesulfonamides containing alkyl substituents leads to the formation of potential dual-action agents with comparable glucose-lowering properties and stronger anti-coagulant activity than the parent drug, metformin.
Highlights
IntroductionDrugs were largely discovered with the use of the “one molecule–one target–one disease” strategy
In the previous decades, drugs were largely discovered with the use of the “one molecule–one target–one disease” strategy
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Summary
Drugs were largely discovered with the use of the “one molecule–one target–one disease” strategy. It allowed to discover many successful drugs, that are selective for a single target known as “magic bullets.”. Several well-known drugs have appeared to affect more than one molecular target, which proved that their efficacy stems from this multi-target behavior. One such example is imatinib, which was originally developed as a selective inhibitor of the BCR-Abl fusion protein, but was shown to inhibit the non-oncogenic C-Abl kinase [1]. The use of multi-target drugs, or polypharmacology, acknowledges an agent to simultaneously affect multiple targets or processes; either by a single compound or a combination of several molecules binding to different targets associated with the disease [3]
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