{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:56:58Z","timestamp":1791316618049,"version":"4.3.1"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Stichting Erasmus Trusfonds","award":[".101.718"],"award-info":[{"award-number":[".101.718"]}]},{"name":"Stichting Erasmus Trusfonds","award":["015.013.033"],"award-info":[{"award-number":["015.013.033"]}]},{"name":"Stichting Erasmus Trusfonds","award":["202008520048"],"award-info":[{"award-number":["202008520048"]}]},{"name":"Dutch Research Council","award":[".101.718"],"award-info":[{"award-number":[".101.718"]}]},{"name":"Dutch Research Council","award":["015.013.033"],"award-info":[{"award-number":["015.013.033"]}]},{"name":"Dutch Research Council","award":["202008520048"],"award-info":[{"award-number":["202008520048"]}]},{"name":"EUR fellowship of the Erasmus University","award":[".101.718"],"award-info":[{"award-number":[".101.718"]}]},{"name":"EUR fellowship of the Erasmus University","award":["015.013.033"],"award-info":[{"award-number":["015.013.033"]}]},{"name":"EUR fellowship of the Erasmus University","award":["202008520048"],"award-info":[{"award-number":["202008520048"]}]},{"name":"CSC Scholarship","award":[".101.718"],"award-info":[{"award-number":[".101.718"]}]},{"name":"CSC Scholarship","award":["015.013.033"],"award-info":[{"award-number":["015.013.033"]}]},{"name":"CSC Scholarship","award":["202008520048"],"award-info":[{"award-number":["202008520048"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Objectives: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. Methods: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 \u00b5M and 25 \u00b5M against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 &lt; 8 \u00b5M were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. Results: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 \u00b5M and 25 \u00b5M, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. Conclusion: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.<\/jats:p>","DOI":"10.3390\/ijms25116227","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:50:09Z","timestamp":1717588209000},"page":"6227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis"],"prefix":"10.3390","volume":"25","author":[{"given":"Jingyi","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Eadie","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marij","family":"Schippers","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Fahal","sequence":"additional","affiliation":[{"name":"Mycetoma Research Centre, Khartoum 1115, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7530-2113","authenticated-orcid":false,"given":"Beno\u00eet","family":"Laleu","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture, 1215 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Verbon","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8652-8783","authenticated-orcid":false,"given":"Wendy W. J.","family":"van de Sande","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Van de Sande, W.W.J. (2013). Global burden of human mycetoma: A systematic review and meta-analysis. PLoS Neglected Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002550"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1093\/trstmh\/trab032","article-title":"Mycetoma in West Africa","volume":"115","author":"Oladele","year":"2021","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1093\/mmy\/myx061","article-title":"Closing the mycetoma knowledge gap","volume":"56","author":"Fahal","year":"2018","journal-title":"Med. Mycol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Welsh, O., Al-Abdely, H.M., Salinas-Carmona, M.C., and Fahal, A.H. (2014). Mycetoma Medical Therapy. PLoS Neglected Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0003218"},{"key":"ref_5","first-page":"CD013082","article-title":"Drug therapy for Mycetoma","volume":"2018","author":"Scolding","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.trstmh.2010.11.008","article-title":"The safety and efficacy of itraconazole for the treatment of patients with eumycetoma due to Madurella mycetomatis","volume":"105","author":"Fahal","year":"2011","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1111\/myc.13509","article-title":"Epidemiological cut-off values for itraconazole and ravuconazole for Madurella mycetomatis, the most common causative agent of mycetoma","volume":"65","author":"Nyuykonge","year":"2022","journal-title":"Mycoses"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kloezen, W., van Helvert-van Poppel, M., Fahal, A.H., and Van De Sande, W.W.J. (2015). A Madurella mycetomatis Grain Model in Galleria mellonella Larvae. PLoS Neglected Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003926"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1111\/bjd.14025","article-title":"Amphotericin B but not itraconazole is able to prevent grain formation in experimental Madurella mycetomatis mycetoma in mice","volume":"173","author":"Fahal","year":"2015","journal-title":"Br. J. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lim, W., Melse, Y., Konings, M., Duong, H.P., Eadie, K., Laleu, B., Perry, B., Todd, M.H., Ioset, J.-R., and van de Sande, W.W.J. (2018). Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma. PLoS Neglected Trop. Dis., 12.","DOI":"10.1101\/258905"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Samby, K., Willis, P.A., Burrows, J.N., Laleu, B., and Webborn, P.J.H. (2021). Actives from MMV Open Access Boxes? A suggested way forward. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009384"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lim, W., Nyuykonge, B., Eadie, K., Konings, M., Smeets, J., Fahal, A., Bonifaz, A., Todd, M., Perry, B., and Samby, K. (2022). Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma. PLoS Neglected Trop. Dis., 16.","DOI":"10.1371\/journal.pntd.0010159"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1080\/17460441.2022.2080195","article-title":"Identifying novel drugs with new modes of action for neglected tropical fungal skin diseases (fungal skinNTDs) using an Open Source Drug discovery approach","volume":"17","author":"Lim","year":"2022","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kim, T., Hanh, B.-T., Heo, B., Quang, N., Park, Y., Shin, J., Jeon, S., Park, J.-W., Samby, K., and Jang, J. (2021). A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115936"},{"key":"ref_15","unstructured":"(2024, January 30). MMV about the COVID Box. Available online: https:\/\/www.mmv.org\/mmv-open\/covid-box\/about-covid-box."},{"key":"ref_16","unstructured":"(2024, January 30). MMV about the Global Health Priority Box. Available online: https:\/\/www.mmv.org\/mmv-open\/global-health-priority-box\/about-global-health-priority-box."},{"key":"ref_17","unstructured":"Wang, X., and Frye, S. (2015). Preparation of Pyrazolopyrimidine Compounds as Mer Tyrosine Kinase Inhibitors Useful for Treatment of Cancer, Infections, and Other Diseases. (WO\/2015\/157125)."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1021\/ml200239k","article-title":"Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia","volume":"3","author":"Liu","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejmech.2013.03.035","article-title":"UNC1062, a new and potent Mer inhibitor","volume":"65","author":"Liu","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","unstructured":"Wang, X., and Frye, S. (2015). MerTK-Specific Pyrazolopyrimidine Compounds. (WO\/2015\/157122)."},{"key":"ref_21","unstructured":"Ji, N., Mainolfi, N., and Weiss, M. (2020). MerTK Degraders and Uses Thereof. (WO\/2020\/010210)."},{"key":"ref_22","unstructured":"Hoffman-La Roche, F., Liu, W., Luk, K.-C.T., and Zhang, X. (2012). Pyrazolo Pyrimidines as DYRK1A and DYRK1B Inhibitors. (WO\/2012\/098068)."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kosti, I., Mandel-Gutfreund, Y., Glaser, F., and Horwitz, B.A. (2010). Comparative analysis of fungal protein kinases and associated domains. BMC. Genom., 11.","DOI":"10.1186\/1471-2164-11-133"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"MacAlpine, J., Liu, Z., Hossain, S., Whitesell, L., Robbins, N., and Cowen, L.E. (2023). DYRK-family kinases regulate Candida albicans morphogenesis and virulence through the Ras1\/PKA pathway. mBio, 14.","DOI":"10.1128\/mbio.02183-23"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Van Rhijn, N., Zhao, C., Al-Furajij, N., Storer, I., Valero, C., Gago, S., Chown, H., Baldin, C., Fortune-Grant, R., and Bin Shuraym, H. (2023). Functional analysis of the Aspergillus fumigatus kinome reveals a DYRK kinase involved in septal plugging is a novel antifungal drug target. Res. Sq., rs-2960526.","DOI":"10.21203\/rs.3.rs-2960526\/v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1038\/s41467-021-26390-w","article-title":"A small molecule produced by Lactobacillus species blocks Candida albicans filamentation by inhibiting a DYRK1-family kinase","volume":"12","author":"MacAlpine","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3374","DOI":"10.2174\/1381612829666221102162000","article-title":"Medicinal Chemistry of Pyrazolopyrimidine Scaffolds Substituted with Different Heterocyclic Nuclei","volume":"28","author":"Elgemeie","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1021\/acsinfecdis.3c00199","article-title":"Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris","volume":"9","author":"Pan","year":"2023","journal-title":"ACS Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1244170","DOI":"10.3389\/fimmu.2023.1244170","article-title":"Structure and functions of Mer, an innate immune checkpoint","volume":"14","author":"Ubil","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3508","DOI":"10.4049\/jimmunol.1200662","article-title":"Efficient Clearance of Early Apoptotic Cells by Human Macrophages Requires M2c Polarization and MerTK Induction","volume":"189","author":"Zizzo","year":"2012","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/35075603","article-title":"Phagocytosis and clearance of apoptotic cells is mediated by MER","volume":"411","author":"Scott","year":"2001","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6526","DOI":"10.1073\/pnas.1524292113","article-title":"MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation","volume":"113","author":"Cai","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Blom, K., Rubin, J., Berglund, M., Jarvius, M., Lenhammar, L., Parrow, V., Andersson, C., Loskog, A., Fryknas, M., and Nygren, P. (2019). Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition. BMC Res. Notes, 12.","DOI":"10.1186\/s13104-019-4273-5"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"myad070","DOI":"10.1093\/mmy\/myad070","article-title":"A Falciformispora senegalensis grain model in Galleria mellonella larvae","volume":"61","author":"Ma","year":"2023","journal-title":"Med. Mycol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sheehan, G., Konings, M., Lim, W., Fahal, A., Kavanagh, K., and van de Sande, W.W.J. (2020). Proteomic analysis of the processes leading to Madurella mycetomatis grain formation in Galleria mellonella larvae. PLoS Neglected Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008190"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e00418-16","DOI":"10.1128\/genomeA.00418-16","article-title":"Genome Sequence of Madurella mycetomatis mm55, Isolated from a Human Mycetoma Case in Sudan","volume":"4","author":"Smit","year":"2016","journal-title":"Genome Announc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JCM.02331-20","article-title":"A Short-Tandem-Repeat Assay (MmySTR) for Studying Genetic Variation in Madurella mycetomatis","volume":"59","author":"Nyuykonge","year":"2021","journal-title":"J. Clin. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/trstmh\/traa184","article-title":"In vitro susceptibility testing for black grain eumycetoma causative agents","volume":"115","year":"2021","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"myac003","DOI":"10.1093\/mmy\/myac003","article-title":"Inhibiting DHN- and DOPA-melanin biosynthesis pathway increased the therapeutic value of itraconazole in Madurella mycetomatis infected Galleria mellonella","volume":"60","author":"Lim","year":"2022","journal-title":"Med. Mycol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:54:18Z","timestamp":1760108058000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25116227"],"URL":"https:\/\/doi.org\/10.3390\/ijms25116227","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]}}}