Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase (PfDHODH)

Malaria is one of the three most impacting infectious diseases in the world (together with HIV/AIDS and tuberculosis) and kills millions of people every year.
The absence of effective vaccines and drug resistance emergence for nearly all known antimalarial agents has compromised the efficacy of control programs. Plasmodium falciparum Dihydroorotate Dehydrogenase (PfDHODH) is a clinically validated target for antimalarial drug development. This line of research led us to develop compounds capable of selectively inhibiting PfDHODH, rather than, its human counterpart in the low micromolar range.
This project involves important collaboration with international laboratories such as San Andreas University at La Paz (Bolivia), where activity on parasites is investigated, and Nirma University at Ahmedabad (India), where in vivo tests are performed.

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Collaborations

  • Prof. Vivek K. Vyas, Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad (India)
  • Prof. Alberto Gimenez, Institute of Pharmacognosy & Biochemistry Research, Universidad Mayor De San Andres, La Paz (Bolivia)
  • Prof. Tiziano Tuccinardi, Molecular Modelling and Virtual Screening Laboratory, Dep. of Pharmacy, University of Pisa (IT)
  • Prof. Riccardo Miggiano, Structural biology, Dep. of Drug Sciences, University of Piemonte Orientale, Novara (IT)
  • ATOMWISE, INC., 250 Sutter St., Suite 650, San Francisco, California (USA)

Since 2017, Prof. Marco Lolli and Prof. Vivek Vyas (Nirma University) have worked effectively to create the synergies needed to bring their research groups together: our collaboration is dynamic and encourages students and young scientists to take part in future exchanges for study and research visits. MEDSynth members were already engaged in visiting research and teaching activities at Nirma University, and currently two PhD students of Doctoral Research Scholar, Institute of Pharmacy, Nirma College, Dr. Manmohan Sharma and Dr. Abu Sufiyan Chhipa, are hosted at our group for 9 months each.
Along the way of our Research, we also took some pictures… enjoy our international journey!

UniTO - Nirma University Research Journey

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Representative pubblications

  • M. Sharma, V. Pandey, G. Poli, T. Tuccinardi, M. L. Lolli, V. K. Vyas. A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 1: triazolopyrimidine, isoxazolopyrimidine and pyrrole-based (DSM) compounds. Bioorg Chem. 2024, 146, 107249. doi: 10.1016/j.bioorg.2024.107249


  • Pippione, A.C., Sainas, S., Goyal, P., Fritzson, I., Cassiano, G.C., Giraudo, A., Giorgis, M., Tavella, T.A., Bagnati, R., Rolando, B., Caing-Carlsson, R., Costa, F.T.M., Andrade, C.H., Al-Karadaghi, S., Boschi, D., Friemann, R., Lolli, M.L. Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies. Eur. J. Med. Chem., 2019, 163, 266-280 https://doi.org/10.1016/j.ejmech.2018.11.044


  • Boschi, D., Pippione, A.C., Sainas, S., Lolli, M.L. Dihydroorotate dehydrogenase inhibitors in anti-infective drug research. Eur. J. Med. Chem., 2019, 183, 111681 https://doi.org/10.1016/j.ejmech.2019.111681