The development of multifunctional drugs from anti-inflammatory agents is a promising strategy for people with several inflammation-related comorbidities since such medicines could reduce complications, improve health outcomes and lower healthcare costs. In this study, esters of ibuprofen, cinnamic and salicylic acids were synthesized and characterized by spectroscopic methods, with six new compounds identified. Cytotoxicity and anti-inflammatory properties were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay in mouse-derived peritoneal macrophages, which were obtained following an intraperitoneal injection of 0.5 ml of a 2% starch solution. All the tested compounds were safe up to 50% concentrations (2.41 × 10⁻⁴ to 2.41 mM), and monoethylene glycol di-ibuprofen ( 2 ) displayed the highest toxicity (IC ₅₀ = 4.90 mM). Most compounds were non-toxic below 2.41 mM, and all inhibited nitric oxide (NO) production in a concentration-dependent manner at 0.24 mM. Ibuprofen and cinnamic acid derivatives ( 2 , 3 , 5a and 14 ) exhibited enhanced anti-inflammatory effects, with IC ₅₀ = 0.002 mM for monoethylene glycol mono-ibuprofen ( 3 ), while fatty-acid ester salicylates ( DEW4 ) demonstrated weaker NO inhibition. Antioxidant tests (2,2-diphenyl-1-picrylhydrazyl, ferric reducing ability of plasma and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS)) showed limited activities, with few compounds reducing the ABTS+ radical (0.1 ˂ SC ₅₀ ˂ 0.2 mM). Compounds 3 , 5a , 7 , 12 and 14 are potential new anti-inflammatory drugs, while 2 may have anti-cancer properties.

Background: Type 2 diabetes mellitus (T2DM) is a global health challenge characterized by chronic hyperglycemia and oxidative stress. Pithecellobium dulce root has long been recognized for its antidiabetic potential; however, its specific bioactive constituents and mechanisms of action remain poorly defined. This study aimed to evaluate the antidiabetic and antioxidant properties of extracts and isolated molecules from P. dulce root bark. Methods: The DCM/MeOH crude extract of P. dulce root bark was fractionated with n-hexane (PDEH) and ethyl acetate (PDAE), followed by chromatographic purification and spectroscopic characterization, yielding seventeen compounds (1–17). The antioxidant activity (DPPH, ABTS, FRAP) and antidiabetic potential of PDEH, PDAE, and 1–17 were assessed in vitro using yeast-derived enzymes and in silico (targeting human α-glucosidase [PDB: 2QLY] and human α-amylase [PDB: 4GQR]). The in vitro α-glucosidase experiments used saccharomyces cerevisiae enzyme, which varies from the human target. Therefore, these results should be taken as preliminary screening data that needs confirmation with human enzymes. Results: Compound 1 was identified as new, while 2 was isolated for the first time from a natural source. The cell-free chemical tests DPPH, ABTS, and FRAP measured antioxidant capability. These tests quantify radical-scavenging and electron-transfer capabilities in vitro and are preliminary chemical screening methods. They do not directly represent biological antioxidant activity in cells or organisms. PDEH demonstrated strong radical scavenging against DPPH (IC₅₀ = 15.30 μg/mL) and ABTS (IC₅₀ = 12.80 μg/mL), while pristriol (16) showed ferric reducing power (EC₅₀ = 4200 μM FeSO₄/g). Enzyme inhibition assays demonstrated activity against α-amylase (IC₅₀ 53.88–112.24 µg/mL; acarbose IC₅₀ = 91.20 µg/mL) and α-glucosidase (IC₅₀ 18.38–136.88 µg/mL; acarbose IC₅₀ = 11.31 µg/mL). Compounds 15, 1, and 2 showed superior activity compared to acarbose for α-amylase, with effect sizes (Cohen’s d) of 2.15, 0.94, and 0.82, respectively, and IC₅₀ values of 53.88, 88.15, and 92.62 µg/mL; for α-glucosidase, IC₅₀ values were 18.38, 39.25, and 36.40 µg/mL, respectively. Docking studies supported these findings, revealing binding energies of −9.08, −8.34, and −7.22 kcal/mol for compounds 1, 2, and 15 with α-amylase, and −10.35 and −9.79 kcal/mol for compounds 1 and 2 with α-glucosidase. ADME profiling further identified 1 and 2 as promising lead candidates for dual-enzyme inhibition. Conclusions: P. dulce root bark represents a potent source of bioactive molecules with both antioxidant and dual-enzyme-inhibitory properties. These findings validate its traditional use and highlight its potential in the development of multitarget therapies for T2DM management.