1. Structure Guided Lead Generation of New Antimalarial Drugs
Ahmad Abdelzaher, Safwa Abuelazaym and Toqa Osama.
Supervised by Dr. Reem Arafa.

2. Introduction
Malaria is a mosquito-borne disease caused by a parasite of the plasmodium type.
In 2012, there were around 627,000 malaria deaths worldwide.
Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern.

3. Continued…
Malaria is treated through chemotherapeutic and vector control strategies.
Cambodia–Thailand border strains are
resistant to combination therapies that
include artemisinins.

4. Plasmodium falciparum Thymidylate kinase
pfTMK Catalyzes the phosphorylation of dTMP to dTDP in the presence of ATP and magnesium.
This enzyme is important in the pathway of synthesis of dTTP from dTMP, and hence DNA synthesis.
pfTMK has emerged as an important drug target because of it’s broader specificity than hsTMK.

6. New leads targeting Mtb TMK
All of the TMK inhibitors reported so far are either TMP analogs or contain a thymidine core.
To achieve more potency, a recent paper by Naik et al., 2015 invested in HTS and FBLG against Mtb TMK.
Two novel classes of Mtb TMK inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones.

7. 1,6-naphthyridin-2-ones

8. 1,6-naphthyridin-2-ones Optimization

9. 3-cyanopyridones Thymidine : Original Ligand
3-cyanopyridone: Inhibitor

10. Further Optimization

11. 3D image for the interactions. A is TMP and B is 3-cyanopyridones

12. Fused Cyanopyridones

13. Limitations for Fused Cyanopyridones
No Cellular activity.
Could be explained by:
Poor cellular permeability.
Ionic nature of the compounds (COOH)

14. Sulfoxide and sulfone sub-series of the cynanopyridones

15. Conclusion
HTS and FBLG against Mtb TMK resulted in 3-cyanopyridone and 1,6-naphthyridinone.
Structure guided optimization led to compounds with single digit nanomolar potency in vitro, albeit devoid of any cellular activity.

16. Continued…
A sub-series containing sulfoxide or sulfone substituents showed low micromolar Mtb MIC.
Those drugs can be as equally effective against pfTMK and solve the Malaria resistance problem.

17. References
Belen Cassera, M., Zhang, Y., Z. Hazleton, K., & L. Schramm, V. (2011). Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum. CTMC, 11(16), doi: /
Naik, M., Raichurkar, A., Bandodkar, B., Varun, B., Bhat, S., & Kalkhambkar, R. et al. (2015). Structure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors. Journal Of Medicinal Chemistry, 58(2), doi: /jm
Prosite.expasy.org,. (2015). PROSITE. Retrieved 3 February 2015, from
Sinha, S., Medhi, B., & Sehgal, R. (2014). Challenges of drug-resistant malaria. Parasite, 21, 61. doi: /parasite/

18. Thank you.