Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

Design, Synthesis, and Herbicidal Activity of Novel Tetrahydrophthalimide Derivatives Containing Oxadiazole/Thiadiazole Moieties.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to NtPPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.

Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD+-Dependent Lysine Deacylase Sirtuin 2.

The NAD+-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.

New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study.

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).

Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma.

Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC50 = 1.30 µM) and inhibited the proliferation of HCCLM3 cells (IC50 = 3.1 µM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.

One-step synthesis of diaryloxadiazoles as potent inhibitors of BCRP.

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.

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Design, synthesis, in silico and biological evaluation of new indole based oxadiazole derivatives targeting estrogen receptor alpha.

A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC50 values ranging from 1.78 to 19.74 µM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-ß is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC50 = 12.78 ± 0.92 µM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC50 values of 3.24 ± 0.46 and 1.72 ± 1.67 µM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents.

Oxadiazole Derivatives of Diclofenac as an Anti-proliferative Agent for B-cell Non-Hodgkin Lymphoma: An In vitro and In Silico Studies.

BACKGROUND: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies. AIM: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through in vitro and in silico approaches. METHODS: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program. RESULTS: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-ß in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The in silico studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue. CONCLUSION: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-ß-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors.

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-ß-alanine 1,3,4-oxadiazole hybrids (4a-l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-ß-alanine 1,3,4-oxadiazole derivatives 4a-l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.

Exploring the Synergistic Anticancer Potential of Benzofuran-Oxadiazoles and Triazoles: Improved Ultrasound- and Microwave-Assisted Synthesis, Molecular Docking, Hemolytic, Thrombolytic and Anticancer Evaluation of Furan-Based Molecules.

Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole 5a-g and benzofuran-triazole 7a-h derivatives in good to excellent yields (60-96%), in comparison with conventional methods (36-80% yield). These synthesized derivatives were screened for hemolysis, thrombolysis and anticancer therapeutic potential against an A549 lung cancer cell line using an MTT assay. Derivatives 7b (0.1%) and 5e (0.5%) showed the least toxicity against RBCs. Hybrid 7f showed excellent thrombolysis activity (61.4%) when compared against reference ABTS. The highest anticancer activity was displayed by the 5d structural hybridwith cell viability 27.49 ± 1.90 and IC50 6.3 ± 0.7 µM values, which were considerably lower than the reference drug crizotinib (IC50 8.54 ± 0.84 µM). Conformational analysis revealed the spatial arrangement of compound 5d, which demonstrated its significant potency in comparison with crizotinib; therefore, scaffold 5d would be a promising anticancer agent on the basis of cytotoxicity studies, as well as in silico modeling studies.

Second generation ß-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma.

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, ß-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of ß-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the ß-elemene structure and designed six series of new generation ß-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and ß-elemene is a feasible strategy to improve the in vivo anti-tumour activity of ß-elemene.

Neuroprotective evaluation of novel substituted 1,3,4-oxadiazole and aroylhydrazone derivatives.

The paper reports on the facile and convenient synthesis of a series of novel 2,5-substituted 1,3,4-oxadiazoles 3a-f and that of aroylhydrazone-based molecular hybrids 5a-g from readily available starting materials. The structure of the compounds was confirmed by IR, 1H NMR, 13C NMR and HRESI-MS spectral data. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione in rat brain synaptosomes, isolated by Percoll gradient. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine-induced neurotoxicity. Administered alone, at a concentration of 40 µM, most of the 1,3,4-oxadiazole derivatives and all of the hydrazone derivatives exhibited weak statistically significant neurotoxic effects, compared to the control. Two of the compounds from the novel oxadiazoles 3a and 3d did not have any toxicity. In a model of 6-OHDA-induced oxidative stress, again 3a and 3d and all aroylhydrazone derivatives 5a-g revealed statistically significant neuroprotective effect by preserving the synaptosomal viability and the level of reduced glutathione, against the toxic agent. Some of the compounds may have neuroprotective effects due to possible stabilization of the synaptosomal membrane and/or because of the preserved reduced glutathione. Additionally, all the compounds display a good predicted ADME profile.

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.

Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity.

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 µM against L. infantum amastigote forms and CC50 value superior to 500 µM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 µM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.

Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

Self-Assembly Dual-Responsive NO Donor Nanoparticles for Effective Cancer Therapy.

Drug resistance and the serious side effects caused by classical chemotherapy drugs necessitate the development of novel targeted drug delivery systems. The high lipophilicity and short half-life of nitric oxide (NO), a gas with strong antitumor activity, make it difficult to reach the tumor site and result in a poor therapeutic effect in vivo. In order to overcome the deficiencies of the existing NO donors and NO delivery vehicles, a novel strategy was proposed to deliver NO for cancer chemotherapy by the prodrug dimer self-assembly nanoparticles of NO donors. Specifically, phenylsulfonylfuroxan (FZ) was chosen as the NO donor to synthesize the prodrug dimer precursor (FZ-SS-FZ) by disulfide linkages and ester bonds. The insertion of disulfide linkages promotes the self-assembly of FZ-SS-FZ in water. After this, the dual-responsive and tumor-targeting NO delivery system (FZ-SS-FZ@FA NPs) will finally be fabricated by further introducing folic acid on the surface of nanoparticles. FZ-SS-FZ can self-assemble to form uniform nanoparticles in water, which can effectively deliver NO to the tumor site and be uptaken by tumor cells, thus resulting in specific NO release in tumor cells and inducing tumor cell apoptosis. FZ-SS-FZ@FA NPs significantly improve the drug loading and delivery efficiencies of NO for chemotherapy, while enhancing its efficacy, providing a novel strategy for the tumor-targeted delivery of NO and at the same time laying a theoretical basis for the clinical translation of NO-based gas chemotherapy, opening up a new approach for cancer chemotherapy.

In-vitro cytotoxic evaluation of newly designed ciprofloxacin-oxadiazole hybrids against human liver tumor cell line (Huh7).

Fluoroquinolones are targets of interest due to their broad spectrum antibacterial activity. Structure-activity relationship (SAR) of fluoroquinolones clearly indicates that substitution at C-7 position enhances the lipophilicity of these scaffolds resultantly affording pharmacologically significant compounds. Therefore, various ciprofloxacin-oxadiazole hybrids were synthesized and characterized by spectral analysis. Cytotoxic activity of these derivatives was assessed using human liver tumor cells (Huh7). One dose anticancer test results revealed moderate cytotoxicity of the newly synthesized compounds against this cell line. As the only compound 4a depicted comparatively lower cell viability value (81.91% using 100µg/mL concentration) than the other compounds.

Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction.

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their activities in vitro and vivo to find potent inhibitors of the PD-1/PD-L1 interaction. Among them, compoundⅡ-14exhibited outstanding biochemical activity, with an IC50of 0.0380 µM. Importantly, compound II-14, with a TGI value of 35.74 %, had more potent efficacy in a mouse tumor model compared to that in the control group. Surprisingly, when compound II-14 combined with 5-FU in a mouse tumor model having a TGI value of 64.59 %, which showed potential anti-tumor synergistic effects. Furthermore, immunohistochemistry analysis demonstrated thatcompound II-14 activated the immune microenvironment by promoting the infiltration of CD4+ T cells into tumor tissues. These results indicate that compound II-14 is a promising lead compound for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.

Glycocalixarene with luminescence for Warburg effect-mediated tumor imaging and targeted drug delivery.

Fluorescently labeled calix[4]arene glycoconjugates demonstrate multifunctional potential in both Warburg effect mediated tumor imaging and GLUT1 targeted drug delivery. Nitrobenzoxadiazole and mannose conjugated NBD-Man-CA was found to be selectively recognized by GLUT1 and act as a "molecular carrier" for selective tumor targeting.

Structure-based screening for the discovery of 1,2,4-oxadiazoles as promising hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways.

The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC50 values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1ß and TNF-α. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis.