**4. Conclusions**

Overall, we reported the synthesis and evaluation of novel Tdp1 inhibitors that combine the arylcoumarin and monoterpenoid moieties. Our results found that these compounds are good Tdp1 inhibitors with IC<sup>50</sup> in the submicromolar or low submicromolar ranges. Compound **3ba** showed a significant increase in the antitumor effect of tpc on Krebs-2 ascites in an in vivo tumor model. In addition, these compounds presented the good physicochemical properties required for oral bioavailability, making them good candidates for further development. Thus, this type of arylcoumarin-monoterpenoid hybrids represents an excellent starting point for the further development of adjuvant therapy against cancer in combination with Top 1 poisons.

**Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/1422-0067/21/1/126/s1.

**Author Contributions:** Chemistry investigation, T.M.K., D.V.K. and K.P.V.; In vitro investigation, A.L.Z.; A.A.C., E.S.I., O.D.Z., J.P., I.K.H.L.; In vivo investigation, V.I.K., V.P.N., N.A.P., Modeling, J.R., R.C., D.M.A.-T.; Methodology, N.F.S. and O.I.L.; Project administration, K.P.V.; Supervision, K.P.V.; Writing—original draft, A.L.Z. and T.M.K.; Writing—review & editing, K.P.V., J.R., I.K.H.L., N.F.S., O.I.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was funded by the Russian Science Foundation grant N◦ 19-13-00040. A.A. Chepanova is grateful to Russian State funded budget project of ICBFM SB RAS N<sup>o</sup> AAAA-A17-117020210022-4 for financial support for Tdp1 purification.

**Acknowledgments:** Authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
