{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:15:56Z","timestamp":1760148956988,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["602666","201506220185","CA21111"],"award-info":[{"award-number":["602666","201506220185","CA21111"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["602666","201506220185","CA21111"],"award-info":[{"award-number":["602666","201506220185","CA21111"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Excellence Centre \u2018Infla-Med\u2019","award":["602666","201506220185","CA21111"],"award-info":[{"award-number":["602666","201506220185","CA21111"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC50 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 &gt; 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.<\/jats:p>","DOI":"10.3390\/molecules28134939","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T05:11:54Z","timestamp":1687756314000},"page":"4939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structural Optimization of BIPPO Analogs as Potent Antimalarials"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7035-8807","authenticated-orcid":false,"given":"Yang","family":"Zheng","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7507-1634","authenticated-orcid":false,"given":"An","family":"Matheeussen","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-9509","authenticated-orcid":false,"given":"Louis","family":"Maes","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3202","authenticated-orcid":false,"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geert Jan","family":"Sterk","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1354-2848","authenticated-orcid":false,"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/S0140-6736(18)30324-6","article-title":"Malaria","volume":"391","author":"Ashley","year":"2018","journal-title":"Lancet"},{"key":"ref_2","unstructured":"(2023, May 28). World Health Organization World Malaria Report. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240015791."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.1016\/j.vaccine.2010.05.033","article-title":"The RTS,S Malaria Vaccine","volume":"28","author":"Casares","year":"2010","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(15)60721-8","article-title":"Efficacy and Safety of RTS,S\/AS01 Malaria Vaccine with or without a Booster Dose in Infants and Children in Africa: Final Results of a Phase 3, Individually Randomised, Controlled Trial","volume":"386","author":"Rts","year":"2015","journal-title":"Lancet"},{"key":"ref_5","unstructured":"WHO (2016). Malaria Position Paper. Wkly. Epidemiol. Rec., 91, 33\u201352."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1016\/S0140-6736(21)01065-5","article-title":"R21\/Matrix-M: A Second Malaria Vaccine?","volume":"397","author":"Moorthy","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/S0140-6736(13)60310-4","article-title":"The Changing Epidemiology of Malaria Elimination: New Strategies for New Challenges","volume":"382","author":"Cotter","year":"2013","journal-title":"Lancet"},{"key":"ref_8","unstructured":"(2023, May 28). World Health Organization World Malaria Report. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789241565653."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Delves, M., Plouffe, D., Scheurer, C., Meister, S., Wittlin, S., Winzeler, E.A., Sinden, R.E., and Leroy, D. (2012). The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites. PLoS Med., 9.","DOI":"10.1371\/journal.pmed.1001169"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","article-title":"Antimalarial Drug Resistance: Linking Plasmodium Falciparum Parasite Biology to the Clinic","volume":"23","author":"Blasco","year":"2017","journal-title":"Nat. Med."},{"key":"ref_11","unstructured":"(2023, May 28). World Health Organization Antimalarial Drug Combination Therapy: Report of a WHO Technical Consultation. Available online: https:\/\/apps.who.int\/iris\/handle\/10665\/66952."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1021\/cb501004q","article-title":"Identification of Potent Phosphodiesterase Inhibitors That Demonstrate Cyclic Nucleotide-Dependent Functions in Apicomplexan Parasites","volume":"10","author":"Howard","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.bmcl.2009.03.024","article-title":"The Discovery of Potent, Selective, and Orally Bioavailable PDE9 Inhibitors as Potential Hypoglycemic Agents","volume":"19","author":"DeNinno","year":"2009","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1080\/00397910903061043","article-title":"Novel Method of Reducing Ketones Using Sodium Hydroxide in Isopropanol","volume":"40","author":"Zuidema","year":"2010","journal-title":"Synth. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1002\/adsc.200700091","article-title":"A Simple and Efficient Catalytic Method for the Reduction of Ketones","volume":"349","author":"Wettergren","year":"2007","journal-title":"Adv. Synth. Catal."},{"key":"ref_16","unstructured":"DeNinno, M.P., Hughes, B., Kemp, M.I., Palmer, M.J., and Wood, A. (2003). PDE9 Inhibitors for Treating Cardiovascular Disorders. (US20030195205A1), Patent."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1016\/S0960-894X(03)00631-0","article-title":"Pyrazolo[4,3-d]Pyrimidines as New Generation of Cyclin-Dependent Kinase Inhibitors","volume":"13","author":"Moravec","year":"2003","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_18","unstructured":"Moravcova, D., Havlicek, L., Krystof, V., Lenobel, R., Binarova, P., Mlejnek, P., Vojtesek, B., Uldrijan, S., Schmulling, T., and Strnad, M. (2004). Pyrazolo [4,3-d] Pyrimidines, Processes for Their Preparation and Methods of Use. (EP1475094B1), Patent."},{"key":"ref_19","unstructured":"Moravcov\u00e1, D., Havlicek, L., Krystof, V., Lenobel, R., and Strnad, M. (2003). Pyrazolo[4,3-d]Pyrimidines, Processes for Their Preparation and Methods for Therapy. (EP1348707A1), Patent."},{"key":"ref_20","unstructured":"Moszczynski-Petkowski, R., Bojarski, L., MAJER, J., Wieczorek, M., DUBIEL, K., and Lamparska-Przybysz, M. (2014). Pyrazolo[4,3-d]Pyrimidin-7(6H)-One Derivatives as PDE9 Inhibitors. (WO2014024125A1), Patent."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pereira, M., Caljon, G., Gouveia, M.J., Maes, L., and Vale, N. (2021). Synthesis, Biological Activity and In Silico Pharmacokinetic Prediction of a New 2-Thioxo-Imidazoldidin-4-One of Primaquine. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030196"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.ejmech.2018.12.050","article-title":"Revisiting Tubercidin against Kinetoplastid Parasites: Aromatic Substitutions at Position 7 Improve Activity and Reduce Toxicity","volume":"164","author":"Hulpia","year":"2019","journal-title":"Eur. J. Med. 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