Abstract
Infectious diseases such as tuberculosis and leishmaniasis are leading causes of human death. One of the major factors contributing to the poor control of these diseases is primarily the reduced effectiveness of the existing chemotherapies as result of the increasing rise of multidrug-resistant strains of their causative agents. This leads to the imperative need to develop new and effective drugs. In search for such agents, a series of hydroquinone-triazole hybrids was investigated. The design, synthesis, and biological activities against the human virulent H37Rv strain of Mycobacterium tuberculosis (Mtb) and Leishmaniasis major (L. major), causative pathogen of human cutaneous leishmaniasis, are herein reported. The hybrids were synthesized following a two-step process Michael addition and Click chemistry. They were found to be noncytotoxic toward human kidney embryonic cells but expressed poor cellular antileishmanial and antimycobacterial activities. Hybrid 14, 2‐{4‐[(phenylsulfanyl)methyl]‐1H‐1,2,3‐triazol‐1‐yl}benzene‐1,4‐diol, was the most active among synthesized molecules, with MIC90 16 and IC50 23 µM against Mtb and L. major parasite, respectively, but had a poor safety profile, being as toxic to mammalian cells as to mycobacteria and parasites. Thus, compound 14 did not stand as potential anti-infective hit for further investigation. Future endeavor will focus on the investigation of more rigid and flexible hybrids of both scaffolds in order to assess the impact a spacer might have on their biological activity.
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Acknowledgements
The authors thank Dr D. Otto for NMR and Dr JHL Jordaan for MS analyses. The following reagent was obtained through BEI Resources, NIAID, NIH: Leishmania major, Strain IR-173 (MHOM/IR/-173), NR-48816.
Funding
This work was funded by South African National Research Foundation Grant to DDN (UID 98937 and 115349) and the North-West University. All TB screening work in the MMRU (UCT) is supported by the South African Medical Research Council (SAMRC) with funds from the South African National Treasury under its Economic Competitiveness and Support Package through the Strategic Health Innovation Partnerships (SHIP) initiative (to DFW).
Author contributions
Conceptualization: DDN; methodology: [C-MH, JA, FJS, RS, AJ, and DFW; formal analysis and investigation: DDN, JA, and DFW; writing original draft preparation: C-MH; writing, reviewing and editing: DDN; funding acquisition: DDN and DFW; resources: DDN and DFW; supervision: DDN.
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This research project was conducted under the institutional ethical approval NWU-00141-14-A5.
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Horn, CM., Aucamp, J., Smit, F.J. et al. Synthesis and in vitro antimycobacterial and antileishmanial activities of hydroquinone-triazole hybrids. Med Chem Res 29, 1387–1399 (2020). https://doi.org/10.1007/s00044-020-02553-0
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DOI: https://doi.org/10.1007/s00044-020-02553-0