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. 2024;16(17):1761-1776.
doi: 10.1080/17568919.2024.2379232. Epub 2024 Sep 4.

Novel 3-substituted coumarins inspire a custom pharmacology prediction pipeline: an anticancer discovery adventure

Islam K Matar  1   2 , Zeinab A Muhammad  3 , Sobhi M Gomha  4 , Sami A Al-Hussain  5 , Maha Al-Ali  5 , Magdi Ea Zaki  5 , Ahmed S El-Khouly  6   7
Affiliations

Novel 3-substituted coumarins inspire a custom pharmacology prediction pipeline: an anticancer discovery adventure

Islam K Matar et al. Future Med Chem. 2024.

Abstract

Aim: This research aims to expand the established pharmacological space of tumor-associated carbonic anhydrases (TACAs) by exploring the synthetically accessible chemical space of 3-substituted coumarins, with the help of in silico pharmacology prediction.Materials & methods: 52 novel 3-substituted coumarins were sketched, prioritizing synthetic feasibility. Their pharmacological potentials were estimated using a custom machine-learning approach. 17 compounds were predicted as cytotoxic against HeLa cells by interfering with TACAs. Those compounds were synthesized and biologically tested against HeLa cells. The three most potent compounds were assayed against multiple carbonic anhydrases, and their enzyme binding mechanism(s) were studied using molecular docking.Results: Experimental results exhibited pronounced consensus with in silico pharmacology predictions.Conclusion: Novel 3-substituted coumarins are herein dispatched to the cancer therapeutics space.

Keywords: antitumor activity; carbonic anhydrases; coumarins; hydrazonoyl chlorides; pharmacological space; thiazol derivatives.

Plain language summary

[Box: see text].

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Conflict of interest statement

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Diagrammatic scheme of synthesis of (A) chalcones 7a-e (B) pyrazole derivatives 8a-d and 9a-c (C) fused pyrimidine derivatives 12, 15 and 18 (D) fused pyrimidine derivatives 20 and 22.
Figure 1.
Figure 1.
Diagrammatic scheme of synthesis of (A) chalcones 7a-e (B) pyrazole derivatives 8a-d and 9a-c (C) fused pyrimidine derivatives 12, 15 and 18 (D) fused pyrimidine derivatives 20 and 22.
Figure 1.
Figure 1.
Diagrammatic scheme of synthesis of (A) chalcones 7a-e (B) pyrazole derivatives 8a-d and 9a-c (C) fused pyrimidine derivatives 12, 15 and 18 (D) fused pyrimidine derivatives 20 and 22.
Figure 2.
Figure 2.
The chemical space resulting from the upstream stage of our pharmacology prediction pipeline. The similarity heatmap comprises 148,943 data points; each point representing an individual chemical compound. The color scale illustrates the spectrum of chemical similarity possessed by the chemical entities of this SkeletonSpheres space in reference to compound 15. The data points were spatially organized on the map using the rubber band scaling algorithm of DataWarrior.
Figure 3.
Figure 3.
Overlay of docked poses for selected novel compounds. (A) Docking poses overlay of the intact coumarins 15, 20 and 22. (B) Docking poses overlay of the hydrolyzed coumarins 15h, 20h and 22h.
Figure 4.
Figure 4.
3D and 2D presentation of hydrolyzed coumarin 15h binding interactions with CAXII.
Figure 5.
Figure 5.
A Structure-activity relationship (SAR) analysis of the synthesized compounds.
See this image and copyright information in PMC

References

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