ABSTRACT
Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17 µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and other diseases where COX-2 plays important role in their pathophysiology.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Bumetanide/analogs & derivatives , Bumetanide/pharmacology , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Bumetanide/chemical synthesis , Bumetanide/therapeutic use , Catalytic Domain/drug effects , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/therapeutic use , Drug Design , Edema/drug therapy , Edema/metabolism , Male , Mice , Molecular Docking Simulation , Rats , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , BenzenesulfonamidesABSTRACT
Molecular cocrystals are of growing interest in pharmaceutics for their improved physicochemical properties. Their mechanochemical synthesis is very promising, being easy, cheap, and "green". Here, for the first time, we report on cocrystallization of bumetanide, a diuretic and natriuretic active principle, and 4-aminobenzoic acid. The synthesis is performed both by wet and dry grinding. The cocrystal formation was investigated with a wide range of techniques, including solid-state NMR, IR, XRD, microscopy, and thermal analysis. Wet and dry grinding procedures led to different cocrystal polymorphs. In particular, the dry method gave a cocrystal by powder amorphization and subsequent crystallization. DFT calculations at the B3LYP/6-31+G(d,p) level of theory shed light on the H-bond scheme at the basis of cocrystal formation. The cocrystals showed improved solubility and dissolution rate with respect to the drug alone. This could guarantee a faster absorption and a better bioavailability of the active principle.
Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Bumetanide/chemical synthesis , 4-Aminobenzoic Acid/chemistry , Bumetanide/chemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Mechanical Phenomena , Microscopy, Electron, Scanning , Models, Chemical , Molecular Structure , Photomicrography , Solubility , Solutions , Spectroscopy, Fourier Transform Infrared , Temperature , Vibration , Water/chemistry , X-Ray DiffractionABSTRACT
The steps in the evolution of sulfamoyl diuretics in current clinical use are outlined. The development was initiated by the chance observation of a clinical side effect of sulfanilamide, which became the first sulfamoyl group (-SO2NH2)-bearing compound used for diuretic treatment of patients. Ensuing chemical synthesis over the past three decades led to the development of three types of sulfamoyl diuretics:carbonic anhydrase inhibitors, thiazides, and the loop or high-ceiling saluretic agents represented by furosemide and bumetanide. The structural relationship of furosemide to sulfanilamide and the thiazide-type diuretics and, for bumetanide, the more specific structure for loop diuretic activity are discussed.
