Li(I), Na(I), and K(I) tolfenamate complexes: Synthesis, characterization, and evaluation of antimicrobial, antioxidant, cytotoxic, and analgesic activities

Tolfenamic acid (tolfH) complexes with Li(I), Na(I), and K(I) were synthesized and characterized through various analytical techniques, including molar conductance measurement, CHN analysis, FTIR, UV, 1 H-NMR spectroscopy, thermal (TGA, DTG, DTA, and DSC) analysis, and powder X-ray diffraction (XRD) studies. Based on the findings of these analyses, the probable formulae for the complexes are [Li(H 2 O) 3 (tolf)].H 2 O, [Na(H 2 O) 6 ][Na(H 2 O) 2 (tolf) 2 ].2H 2 O, and [K(H 2 O) 6 ][K(tolf) 2 ]. The reaction of tolfH with MOH results in the formation of a deprotonated tolf − ion that complexes with the Li(I) ion monodentately through the carbonyl oxygen, while it reacts bidentately with Na(I) and K(I) via the carboxylate anion. The thermal stability of these metal-ion complexes varies, with the loss of crystalline and coordinated water. The average crystallite sizes of the complexes, as determined by XRD, range from 55 to 97 nm. Biological activity assessment shows that the complexes possess antimicrobial and antioxidant activity (IC 50 : 13–16 µg/mL), low toxicity, and improved central and peripheral analgesic effects compared with tolfenamic acid alone. The complexes also exhibited anticancer activity against HeLa cancer cell lines, with LC 50 values ranging from 49.0 to 56.0 μg/mL. Pharmacokinetic and toxicity profiles for the synthesized compounds were predicted by ADMET analysis, suggesting Li-tolf is the superior pharmacokinetic candidate among the three.