A series of 2,4-diaryl-5(4H)-imidazolones were prepared and evaluated for their anti-inflammatory activities. Some selected 2,4-diaryl-5(4H)-imidazolones exhibited excellent anti-inflammatory activity in the carrageenan-induced rat paw edema model. Structure Activity Relationships within the series were studied. The substitution at the N-sulfonamide moiety by a small hydrophilic acetyl group resulted in compounds with superior in vivo anti-inflammatory properties. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 3-day treatment of 25 mg/kg/day.

Diabetes is a chronic fast-growing metabolic disorder that is characterized by high blood glucose levels. Tagetes minuta L. has been used as a traditional remedy for various illnesses for many years, and, furthermore, its oil is used in the perfume and flavor industries. T. minuta contains various metabolites, such as flavonoids, thiophenes, terpenes, sterols, and phenolics, with varied bioactivities. Flavonoids can inhibit carbohydrate-digesting enzymes, such as alpha-amylase, which is a convenient dietary strategy for controlling hyperglycemia. In the current investigation, the isolated flavonoids quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside), quercetagetin-7-O-β-D-glucopyranoside, quercetagetin-6-O-β-D-glucopyranoside, minutaside A, patuletin-7-O-β-D-glucopyranoside, quercetagetin-7-methoxy-6-O-β-D-glucopyranoside, tagenols A and B, quercetagetin-3,7-dimethoxy-6-O-β-D-glucopyranoside, patuletin, quercetin-3,6-dimethyl ether, and quercetin-3-methyl ether from T. minuta were assessed for their alpha-amylase inhibition (AAI) efficacy using an in vitro assay, as well as molecular docking, dynamics simulation, and ADMET analyses. Our findings show that quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside) (1), quercetagetin-7-O-β-D-glucopyranoside (2), quercetagetin-6-O-β-D-glucopyranoside (3), minutaside A (4), patuletin-7-O-β-D-glucopyranoside (5), and quercetagetin-7-methoxy-6-O-β-D-glucopyranoside (6) had a notable AAI capacity (IC₅₀s ranged from 7.8 to 10.1 μM) compared to acarbose (IC₅₀ 7.1 μM). Furthermore, these compounds with the highest binding affinity among the tested flavonoids revealed high docking scores for AA (ranging from −12.171 to 13.882 kcal/mol) compared to that of acarbose (−14.668 kcal/mol). In MDS, these compounds were observed to show maximum stability and the greatest binding free energy, suggesting that they may contend with native ligands. In addition, the ADMET analysis showed that these active compounds had a broad span of drug-like, pharmacokinetic, and physicochemical features and did not possess any considerable undesired effects. The current results suggest the potential of these metabolites as AAI candidates. However, further in vivo and mechanistic studies are warranted to specify the efficacy of these metabolites.

P-glycoprotein (Pgp) is a membrane bound efflux pump spread in a variety of tumor cells and considered as a main component of multidrug resistance (MDR) to chemotherapies. In this work, three groups of compounds (imidazolone, oxazolone and vinyl dipeptide derivatives) were synthesized aiming to develop a molecular framework that effectively suppresses MDR. When tested for their influence on Pgp activity, four compounds coded Cur1-01, Cur1-12V, Curox-1 and Curox-3 significantly decreased remaining ATP concentration indicating Pgp substrate site blocking. On the other hand, Cur-3 and Cur-10 significantly increased remaining ATP concentration, which is indicative of Pgp ATPase inhibition. The cytotoxicity of synthesized compounds was examined against Pgp expressing/highly resistant colorectal cancer cell lines (LS-174T). Compounds Cur-1 and Cur-3 showed considerable cytotoxicity with IC₅₀ values of 7.6 and 8.9 μM, respectively. Equitoxic combination (at IC₅₀ concentrations) of PTX and Cur-3 greatly diminished resistant cell clone from 45.7% to 2.5%, albeit with some drop in potency from IC₅₀ of 7.9 nM to IC₅₀ of 23.8 nM. On the other hand, combination of PTX and the non-cytotoxic Cur1-12V (10 μM) significantly decreased the IC₅₀ of PTX to 3.8 nM as well as the resistant fraction to 16.2%. The combination test was confirmed using the same protocol but on another resistant CRC cell line (HCT-116) as we obtained similar results. Both Cur-3 and Cur1-12V (10 μM) significantly increased the cellular entrapment of Pgp probe (doxorubicin) elevating its intracellular concentration from 1.9 pmole/cell to 3.0 and 2.9 pmole/cell, respectively.

In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC₅₀ = 0.15 µM, while its p-chloro analogue 7b was more active against COX-2 (IC₅₀ = 7.5 µM). The less desirable target COX-1 was inhibited more potently by 8c with IC₅₀ = 7.7 µM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.