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Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents

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Abstract

Two sets of bis-thioureas including a para series (8–14) and a meta series (4, 5, 15–19), were synthesized and evaluated for their anticancer, antimalarial and antimicrobial activities. Most of the synthesized bis-thioureas, except for analogs 8–11, displayed cytotoxicity against MOLT-3 cell line (IC50 = 1.55–32.32 µM). Derivatives 5, 14, 18 and 19 showed a broad spectrum of anticancer activity. Analogs (4, 5, 8, 13, 14, 18 and 19) exhibited higher inhibitory efficacy in HepG2 cells than the control drug, etoposide. Significantly, bis-trifluoromethyl analog 19 was the promising potent cytotoxic agent (IC50 = 1.50–18.82 µM) with the best safety index (1.64–20.60). Antimalarial activity results showed that trifluoromethyl derivative 18 was the most potent compound (IC50 = 1.92 µM, selective index = 6.86). Antimicrobial activity revealed that bis-thioureas 12, 18 and 19 exhibited selective activity against Gram-positive bacteria and fungi. Promisingly, the bis-trifluoromethyl derivative 19 was the most potent compound in the series and displayed higher potency, against most of the Gram-positive bacteria and fungi, than that of ampicillin, the reference drug. Among the tested strains of microorganisms, compound 19 inhibited the growth of Staphylococcus epidermidis ATCC 12228 and Micrococcus luteus ATCC 10240 with the lowest MIC of 1.47 µM. The findings demonstrated that trifluoromethyl group plays a crucial role in their biological activities. Furthermore, the molecular docking was performed to reveal possible binding modes of the compounds against target proteins.

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Acknowledgements

This project is financially supported by Srinakharinwirot University (grant no. 497/2559). Great supports from the office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative are appreciated. We are also indebted to Chulabhorn Research Institute for recording mass spectra and bioactivity testing.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, 10110, Thailand

    Ratchanok Pingaew

  2. Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Nujarin Sinthupoom, Rungrot Cherdtrakulkiat & Virapong Prachayasittikul

  3. Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Prasit Mandi

  4. Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Veda Prachayasittikul & Supaluk Prachayasittikul

  5. Chulabhorn Research Institute, Bangkok, 10210, Thailand

    Somsak Ruchirawat

  6. Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand

    Somsak Ruchirawat

  7. Center of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry of Education, Bangkok, 10400, Thailand

    Somsak Ruchirawat

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  1. Ratchanok Pingaew
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  2. Nujarin Sinthupoom
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Pingaew, R., Sinthupoom, N., Mandi, P. et al. Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents. Med Chem Res 26, 3136–3148 (2017). https://doi.org/10.1007/s00044-017-2008-5

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  • DOI: https://doi.org/10.1007/s00044-017-2008-5

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