**4. Conclusions**

We developed a novel series of DCH-CORMs based on a 1,5-diarylpyrrole scaffold. The screening of three small subsets of 1,5-diarylpyrroles and pyrazoles in a CO release assay allowed us to define the influence of the drug sphere electronic density on the kinetics of CO release. Based on these results, a series of 1,5-diarylpyrroles containing structural fragments of COX-2 selective inhibitors were selected for further biological studies on human primary tendon-derived cells. The observed results suggested the existence of different mechanisms of action and allowed us to conclude that the activities of these compounds result from the combination of COX-inhibition and CO release. Indeed, the obtained data suggest a multiple role for compounds **1**–**5** in tendon-derived diseases: a direct effect on tendon homeostasis and a cytoprotective effect in human tenocytes exposed to oxidative stress, reflecting their activity as CO-releasers, and a reduction of PGE2 secretion, indicating a COX-2 mediated anti-inflammatory effect. Taken together, these findings indicate that these compounds could be potential double-acting therapeutic agents for the management of tendon-related diseases. Further studies are needed to better characterize their composite mechanism of action and the contribution of COX-2 inhibition to their biological activities.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/antiox10111828/s1, Scheme S1: Synthetic pathway for compounds **1**–**5**, Scheme S2: Synthetic pathway for compound **6**, Scheme S3: Synthetic pathway for compound **7**, Scheme S4: Synthetic pathway for compounds **8**,**9**.

**Author Contributions:** F.A., methodology, data curation and formal analysis; S.C. (Sara Consalvi), supervision, formal analysis, writing—original draft and writing—review and editing; S.C. (Simone Carradori), E.B., M.G. and A.G., methodology, data curation and formal analysis; C.C., supervision and formal analysis; S.C. (Simone Carradori) and M.B., conceptualization, funding acquisition, project administration and supervision; G.P., conceptualization, funding acquisition, project administration, supervision, data curation and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work has been supported by the Italian Ministry of Education, Universities and Research—Dipartimenti di Eccellenza—L. 232/2016 and intramural grants to C.C. (FAR2019).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data are contained within the article.

**Conflicts of Interest:** The authors declare no conflict of interest.
