Dual role of azo compounds in inhibiting Plasmodium falciparum adenosine deaminase and hemozoin biocrystallization

ElsevierVolume 243, December 2022, 108384Experimental ParasitologyAbstract

Protein-ligand (GOLD) docking of the NCI compounds into the ligand-binding site of Plasmodium falciparum adenosine deaminase (PfADA) identified three most active azo compounds containing 4-[(4-hydroxy-2-oxo-1H-quinolin-3-yl) moiety. These compounds showed IC50 of 3.7–15.4 μM against PfADA, as well as inhibited the growth of P. falciparum strains 3D7 (chloroquine (CQ)-sensitive) and K1 (CQ-resistant) with IC50 of 1.8–3.1 and 1.7–3.6 μM, respectively. The identified compounds have structures similar to the backbone structure (4-N-(7-chloroquinolin-4-yl)) in CQ, and NSC45545 could mimic CQ by inhibiting the bioformation of hemozoin in parasitic food vacuole. The amount of in situ hemozoin in the ring-stage parasite was determined using a combination of synchrotron transmission Fourier transform infrared microspectroscopy and Principal Component Analysis. Stretching of the C–O bond of hemozoin propionate group measured at 1220–1210 cm−1 in untreated intraerythrocytic P. falciparum strains 3D7 and K1 was disappeared following treatment with 1.85 and 1.74 μM NSC45545, similar to those treated with 0.02 and 0.13 μM CQ, respectively. These findings indicate a novel dual function of 4-[(4-hydroxy-2-oxo-1H-quinolin-3-yl) azo compounds in inhibiting both PfADA and in situ hemozoin biocrystallization. These lead compounds hold promise for further development of new antimalarial therapeutics that could delay the onset of parasitic drug resistance.

Section snippetsDeclarations of interest

This work has been submitted for a Thai Patent, application number 2101002842.

Structure-based virtual screening of PfADA inhibitors from National Cancer Institute (NCI) diversity database

Virtual screening was performed using the GOLD docking program version 5.7.1. (Verdonk et al., 2003). The 1990 compounds for the NCI compound library (http://zinc.docking.org/browse/catalogs/). The crystal structures of PfADA (pdb code: 6II7) (Jaruwat et al., 2019) and of hADA (pdb code: 3IAR) were used in the screening trials. The protonation state of amino acids in the proteins was assigned by GOLD setup wizard. All water molecules were removed. The center of docking area was set around the

Identification of new PfADA inhibitors

The inosine and hypoxanthine binding pockets in PfADA (pdb code: 6II7) were used as a receptor template for GOLD docking experiments (Verdonk et al., 2003). Forty azo compounds from the NCI library were docked with highest calculated tight-binding energy. A known ADA inhibitor 2ʹ-deoxycoformycin and azo compounds NSC45545, NSC45570 and NSC45607 were also docked to the hADA structure and their docking scores were compared with PfADA. The binding affinity of the three azo compounds namely,

Conclusion

Emerging and widespread antimalarial-resistant P. falciparum, including to CQ, in many areas worldwide have resulted in reduced effectiveness of all currently administrated malarial drugs. Therefore, there is an urgent need to search for new parasitic targets and advanced development of novel inhibitors. In the purine salvage pathway, PfADA catalyzes the deamination of adenosine and 5ʹ-methylthioadenosine, but hADA acts only on adenosine (Ting et al., 2005), leading to the synthesis of specific

Author contributions

Buabarn Kuaprasert: Conceptualization, Funding acquisition, Project administration, Methodology, Investigation, Formal analysis, Resource, Writing - Original draft preparation. Penchit Chitnumsub: Supervision, Resources, Writing - Review & Editing. Ubolsree Leartsakulpanich: Supervision, Resources, Writing - Review & Editing. Wipa Suginta: Supervision, Resources, Writing - Review & Editing. Saovanee Leelayoova: Supervision, Writing - Review & Editing. Mathirut Mungthin: Conceptualization,

Acknowledgements

This project was supported by Synchrotron Light Research Institute (Public Organization) (grant number SLRI 3-62) and Kasetsart University Research and Development Institute, Kasetsart University (grant number FF(KU) 6.64). We gratefully thank Computational Materials Physics (CMP) project, SLRI, Thailand, for computing resources docking facility, the staffs at beamline 4.1 for SR transmission FTIR-MS measurement and the SLRI 3rd Floor Central Lab for equipment. We greatly appreciate Emeritus

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