The global spread of drug resistance in bacteria requires new potent and safe antimicrobial agents. Compounds containing the 1,2,4-triazole ring in their structure are characterised by multidirectional biological activity. A large volume of research on triazole and their derivatives has been carried out, proving significant antibacterial activity of this heterocyclic core. This review is useful for further investigations on this scaffold to harness its optimum antibacterial potential. Moreover, rational design and development of the novel antibacterial agents incorporating 1,2,4-triazole can help in dealing with the escalating problems of microbial resistance.

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.

Pyrimidine derivatives exhibit a wide range of biological activities, including anti-inflammatory properties. The aim of this study was to investigate the effects of tested pyrimidine derivatives on the activity of cyclooxygenase isoenzymes (COX-1 and COX-2), antioxidant properties, and their ability to inhibit the growth of inflammatory cells. In vitro tests were conducted to assess the ability of pyrimidine derivatives L1–L4 to inhibit COX-1 and COX-2 activity using the TMPD oxidation assay (N,N,N′,N′-tetramethyl-p-phenylenediamine). The compounds’ ability to inhibit the growth of lipopolysaccharide (LPS)-stimulated THP-1 (human leukemia monocytic) monocyte cells and their impact on reactive oxygen species (ROS) levels in an inflammatory model were also evaluated. The binding properties of human serum albumin (HSA) were assessed using UV–Vis spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC). Among the tested pyrimidine derivatives, L1 and L2 showed high selectivity towards COX-2, outperforming piroxicam and achieving results comparable to meloxicam. In the sulforhodamine B (SRB) assay, L1 and L2 demonstrated dose-dependent inhibition of LPS-stimulated THP-1 cell growth. Additionally, ROS assays indicated that these compounds reduced free radical levels, confirming their antioxidant properties. Binding studies with albumin revealed that L1 and L2 formed stable complexes with HSA. These results suggest that these compounds could serve as a basis for further research into anti-inflammatory and anticancer drugs with reduced toxicity.

In this research, a series of novel hybrid structures of dimethylpyridine-1,2,4-triazole Schiff bases were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, HT29) and normal colonic epithelial cells (CCD 841 CoN). Schiff base 4h was the most potent compound against gastric EPG cancer cells (CC₅₀ = 12.10 ± 3.10 μM), being 9- and 21-fold more cytotoxic than 5-FU and cisplatin, respectively. Moreover, it was not toxic to normal cells. Regarding the cytotoxicity against colorectal cancer cells, compounds 4d and 4l exhibited good activity against HT29 cells (CC₅₀ = 52.80 ± 2.80 μM and 61.40 ± 10.70 μM, respectively), and were comparable to or more potent than cisplatin and 5-FU. Also, they were less toxic to normal cells with a higher selectivity index (SI, CCD 841 CoN/HT29 = 4.20 and 2.85, respectively) than reference drugs (SI, CCD 841 CoN/HT29 < 1). Selected Schiff bases were subjected to the P-glycoprotein inhibition assay. Schiff bases 4d, 4e, and 4l influenced P-gp efflux function, significantly increasing the accumulation of rhodamine 123 in colon cancer cell lines. Further mechanistic studies showed that compound 4l induced apoptotic cell death through a caspase-dependent mechanism and by regulating the p53-MDM2 signaling pathway in HT29 cells. Also, physicochemical predictions of compounds 4d, 4e, 4h, and 4i were examined in silico. The results revealed that the compounds possessed promising drug-likeness profiles.