{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:57:23Z","timestamp":1764831443300,"version":"3.46.0"},"reference-count":67,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT), I.P."},{"name":"R&D unit Global Health and Tropical Medicine","award":["UID\/04413\/2025"],"award-info":[{"award-number":["UID\/04413\/2025"]}]},{"name":"Associated Laboratory in Translation and Innovation Towards Global Health REAL","award":["LA\/P\/0117\/2020"],"award-info":[{"award-number":["LA\/P\/0117\/2020"]}]},{"name":"Programa Para\u00edba sem Fronteiras da Funda\u00e7\u00e3o de Apoio \u00e0 Pesquisa do Estado da Para\u00edba"},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["150103\/2025-5"],"award-info":[{"award-number":["150103\/2025-5"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Malaria is a tropical disease mainly caused by Plasmodium falciparum and represents a global public health problem, with over 200 million cases and 500 thousand deaths reported worldwide. Considering its treatment limitations, it is essential to develop new compounds against malaria. In this context, acridine derivatives are privileged structures. Methods: Thus, new spiroacridines containing N-acylhydrazone (AMTAC) and N-phenylacetamide (ACMD) were synthesized and evaluated in malaria and cytotoxicity assays, as well as in silico studies. Results: As a result, five spiroacridines showed inhibitory activity over 70% against the P. falciparum 3D7-GFP strain at 10 \u03bcM, along with an IC50 range of 2\u20134 \u03bcM. After a brief Structure\u2013Activity Relationship (SAR) analysis, it was observed that the spiroacridine structure must be associated with the hydrazone moiety to successfully inhibit parasite growth. In addition, these molecules presented promising resistance profile, with selectivity for the parasite. After computational studies, spiroacridines showed better affinity with dihydrofolate reductase (DHFR), overcoming the quadruple mutant resistance to pyrimethamine, with more stability in complex with the enzyme. Conclusions: Therefore, the potential of spiroacridines against malaria, with moderate resistance and selectivity profile, as well as DHFR inhibition greater than pyrimethamine, was confirmed.<\/jats:p>","DOI":"10.3390\/antibiotics14121214","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T08:44:28Z","timestamp":1764751468000},"page":"1214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Antimalarial Evaluation of New Spiroacridine Derivatives"],"prefix":"10.3390","volume":"14","author":[{"given":"Misael de Azevedo Teot\u00f4nio","family":"Cavalcanti","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"},{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2904-036X","authenticated-orcid":false,"given":"Sonaly Lima","family":"Albino","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"},{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"given":"Karla Joane da Silva","family":"Menezes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7893-9136","authenticated-orcid":false,"given":"Wallyson Junio Santos","family":"de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"given":"Fernanda de Fran\u00e7a Genu\u00edno Ramos","family":"Campos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-680X","authenticated-orcid":false,"given":"Malu Maria Lucas","family":"dos Reis","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"},{"name":"Departamento de Qu\u00edmica, Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3906-694X","authenticated-orcid":false,"given":"In\u00eas","family":"Morais","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical (IHMT), Universidade NOVA de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"given":"Denise Maria Figueiredo Ara\u00fajo","family":"Duarte","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical (IHMT), Universidade NOVA de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-4336","authenticated-orcid":false,"given":"Igor Jos\u00e9 dos Santos","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"},{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-2249","authenticated-orcid":false,"given":"Valn\u00eas da Silva","family":"Rodrigues-Junior","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Produtos Naturais e Sint\u00e9ticos Bioativos (PgPNSB), Departamento de Ci\u00eancias Farmac\u00eauticas, Universidade Federal da Para\u00edba (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0313-0778","authenticated-orcid":false,"given":"F\u00e1tima","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical (IHMT), Universidade NOVA de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-3750","authenticated-orcid":false,"given":"Ricardo Ol\u00edmpio de","family":"Moura","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"},{"name":"Laborat\u00f3rio de Desenvolvimento e S\u00edntese de F\u00e1rmacos (LDSF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, PB, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1080\/17460913.2024.2412397","article-title":"Current Trends to Design Antimalarial Drugs Targeting N-Myristoyltransferase","volume":"19","author":"Weber","year":"2024","journal-title":"Future Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115550","DOI":"10.1016\/j.ejmech.2023.115550","article-title":"Exploring N-Myristoyltransferase as a Promising Drug Target against Parasitic Neglected Tropical Diseases","volume":"258","author":"Nascimento","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100258","DOI":"10.1016\/j.clinme.2024.100258","article-title":"Malaria: Past, Present and Future","volume":"24","author":"Salkeld","year":"2024","journal-title":"Clin. Med."},{"unstructured":"World Health Organization (2024). World Malaria Report 2024, World Health Organization.","key":"ref_4"},{"doi-asserted-by":"crossref","unstructured":"Alven, S., and Aderibigbe, B. (2019). Combination Therapy Strategies for the Treatment of Malaria. Molecules, 24.","key":"ref_5","DOI":"10.3390\/molecules24193601"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e00244","DOI":"10.1016\/j.parepi.2022.e00244","article-title":"Current Challenges and Nanotechnology-Based Pharmaceutical Strategies for the Treatment and Control of Malaria","volume":"17","author":"Gujjari","year":"2022","journal-title":"Parasite Epidemiol. Control"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/bcp.14474","article-title":"Advances and Roadblocks in the Treatment of Malaria","volume":"88","author":"Hanboonkunupakarn","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"115694","DOI":"10.1016\/j.ejmech.2023.115694","article-title":"Triazole Hybrid Compounds: A New Frontier in Malaria Treatment","volume":"259","author":"Ravindar","year":"2023","journal-title":"Eur. J. Med. Chem."},{"doi-asserted-by":"crossref","unstructured":"Fonte, M., Tassi, N., Gomes, P., and Teixeira, C. (2021). Acridine-Based Antimalarials\u2014From the Very First Synthetic Antimalarial to Recent Developments. Molecules, 26.","key":"ref_9","DOI":"10.3390\/molecules26030600"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.2174\/1381612826666200701160904","article-title":"Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review","volume":"26","author":"Albino","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11164","DOI":"10.1021\/cr500123g","article-title":"\u201cRecycling\u201d Classical Drugs for Malaria","volume":"114","author":"Teixeira","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ijbiomac.2016.07.057","article-title":"New Spiro-Acridines: DNA Interaction, Antiproliferative Activity and Inhibition of Human DNA Topoisomerases","volume":"92","author":"Lafayette","year":"2016","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ijbiomac.2018.10.175","article-title":"Spiro-Acridine Inhibiting Tyrosinase Enzyme: Kinetic, Protein-Ligand Interaction and Molecular Docking Studies","volume":"122","author":"Menezes","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1007\/s00210-023-02686-0","article-title":"Cytotoxicity of a New Spiro-Acridine Derivative: Modulation of Cellular Antioxidant State and Induction of Cell Cycle Arrest and Apoptosis in HCT-116 Colorectal Carcinoma","volume":"397","author":"Sousa","year":"2024","journal-title":"Naunyn-Schmiedeb. Arch. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5049","DOI":"10.21873\/anticanres.14508","article-title":"Anticancer Effect of a Spiro-Acridine Compound Involves Immunomodulatory and Anti-Angiogenic Actions","volume":"40","author":"Duarte","year":"2020","journal-title":"Anticancer Res."},{"doi-asserted-by":"crossref","unstructured":"Silva, D.K.F., Duarte, S.S., Lisboa, T.M.H., Ferreira, R.C., Lopes, A.L.d.O., Carvalho, D.C.M., Rodrigues-Mascarenhas, S., da Silva, P.M., Segundo, M.A.S.P., and de Moura, R.O. (2019). Antitumor Effect of a Novel Spiro-Acridine Compound Is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action. Molecules, 25.","key":"ref_16","DOI":"10.3390\/molecules25010029"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106244","DOI":"10.1016\/j.jddst.2024.106244","article-title":"Spiro-Acridine Derivative-Loaded PLA Nanoparticles for Colorectal Cancer Treatment","volume":"101","author":"Melo","year":"2024","journal-title":"J. Drug Deliv. Sci. Technol."},{"doi-asserted-by":"crossref","unstructured":"de Sousa, V.M., Duarte, S.S., Ferreira, R.C., de Sousa, N.F., Scotti, M.T., Scotti, L., da Silva, M.S., Tavares, J.F., de Moura, R.O., and Gon\u00e7alves, J.C.R. (2024). AMTAC-19, a Spiro-Acridine Compound, Induces in Vitro Antitumor Effect via the ROS-ERK\/JNK Signaling Pathway. Molecules, 29.","key":"ref_18","DOI":"10.3390\/molecules29225344"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5911","DOI":"10.1016\/j.bmc.2018.10.038","article-title":"Synthesis, DNA and Protein Interactions and Human Topoisomerase Inhibition of Novel Spiroacridine Derivatives","volume":"26","author":"Gouveia","year":"2018","journal-title":"Bioorg. Med. Chem."},{"doi-asserted-by":"crossref","unstructured":"Almeida, F.S., Sousa, G.L.S., Rocha, J.C., Ribeiro, F.F., de Oliveira, M.R., de Lima Grisi, T.C.S., Ara\u00fajo, D.A.M., Nobre, M.S.d.C., Castro, R.N., and Amaral, I.P.G. (2021). In Vitro Anti-Leishmania Activity and Molecular Docking of Spiro-Acridine Compounds as Potential Multitarget Agents against Leishmania Infantum. Bioorg. Med. Chem. Lett., 49.","key":"ref_20","DOI":"10.1016\/j.bmcl.2021.128289"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e202300545","DOI":"10.1002\/cmdc.202300545","article-title":"Spiro-Acridine Compound as a Pteridine Reductase 1 Inhibitor: In Silico Target Fishing and in Vitro Studies","volume":"19","year":"2024","journal-title":"ChemMedChem"},{"doi-asserted-by":"crossref","unstructured":"Albino, S., Nobre, M., da Silva, J., dos Reis, M., Nascimento, M., de Oliveira, M., Borges, T., Albuquerque, L., Kuckelhaus, S., and Alves, L. (2025). Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis. Microorganisms, 13.","key":"ref_22","DOI":"10.3390\/microorganisms13061297"},{"doi-asserted-by":"crossref","unstructured":"de Oliveira Viana, J., Silva e Souza, E., Sbaraini, N., Vainstein, M.H., Gomes, J.N.S., de Moura, R.O., and Barbosa, E.G. (2023). Scaffold Repositioning of Spiro-Acridine Derivatives as Fungi Chitinase Inhibitor by Target Fishing and in Vitro Studies. Sci. Rep., 13.","key":"ref_23","DOI":"10.1038\/s41598-023-33279-9"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jphotobiol.2018.10.016","article-title":"Correlation between DNA\/HSA-Interactions and Antimalarial Activity of Acridine Derivatives: Proposing a Possible Mechanism of Action","volume":"189","author":"Silva","year":"2018","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5388","DOI":"10.1016\/j.bmc.2018.07.024","article-title":"Synthesis, in Vitro and in Vivo Biological Evaluation, COX-1\/2 Inhibition and Molecular Docking Study of Indole-N-Acylhydrazone Derivatives","volume":"26","author":"Moraes","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2174\/1871523021666220729141608","article-title":"Effects of Acylhydrazone Derivatives on Experimental Pulmonary Inflammation by Chemical Sensitization","volume":"21","author":"Ramos","year":"2022","journal-title":"Anti-Inflamm. Anti-Allergy Agents Med. Chem."},{"doi-asserted-by":"crossref","unstructured":"de Lima Porto Ramos, K.R., Silva, J.d.A.G., de Sousa, R.S., de Oliveira Borba, E.F., de Farias Silva, M.G., Albino, S.L., Paz, S.T., Soares da Silva, R., Peixoto, C.A., and dos Santos, V.L. (2025). N-Acyl Hydrazone Derivatives Reduce pro-Inflammatory Cytokines, INOS and COX-2 in Acute Lung Inflammation Model. Chem. Biol. Interact., 420.","key":"ref_27","DOI":"10.1016\/j.cbi.2025.111677"},{"doi-asserted-by":"crossref","unstructured":"Xu, S.-K., Jia, Z.-M., Liu, W.-Q., Gu, Y.-Z., Xi, J.-H., Xu, J., Yang, G.-Z., Yang, X.-Z., and Chen, Y. (2024). Synthesis and Antiproliferative Evaluation of New Hybrids of Piperine and Acylhydrazone. Nat. Prod. Res., 1\u20136.","key":"ref_28","DOI":"10.1080\/14786419.2024.2391083"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"139228","DOI":"10.1016\/j.molstruc.2024.139228","article-title":"Synthesis, Characterization, and MAO Inhibitory Activities of Three New Drug-like N-Acylhydrazone Derivatives","volume":"1318","author":"Kaynak","year":"2024","journal-title":"J. Mol. Struct."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ijpddr.2017.03.002","article-title":"Interactions between Tafenoquine and Artemisinin-Combination Therapy Partner Drug in Asexual and Sexual Stage Plasmodium falciparum","volume":"7","author":"Kemirembe","year":"2017","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12936-018-2281-x","article-title":"New Endoperoxides Highly Active in Vivo and in Vitro against Artemisinin-Resistant Plasmodium falciparum","volume":"17","author":"Lobo","year":"2018","journal-title":"Malar. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116056","DOI":"10.1016\/j.ejmech.2023.116056","article-title":"Plasmodium falciparum Topoisomerases: Emerging Targets for Anti-Malarial Therapy","volume":"265","author":"Dar","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1021\/cb8002804","article-title":"Exploiting Structural Analysis, in Silico Screening, and Serendipity to Identify Novel Inhibitors of Drug-Resistant Falciparum Malaria","volume":"4","author":"Dasgupta","year":"2009","journal-title":"ACS Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100703","DOI":"10.1016\/j.chphi.2024.100703","article-title":"The Characteristic Structural and Functional Dynamics of P. Falciparum DHFR Binding with Pyrimidine Chemotypes Implicate Malaria Therapy Design","volume":"9","author":"Oluyemi","year":"2024","journal-title":"Chem. Phys. Impact"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/bs.pmbts.2024.05.001","article-title":"Drug Repurposing for Parasitic Protozoan Diseases","volume":"207","author":"Vijayasurya","year":"2024","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ijpddr.2020.07.002","article-title":"Repurposing Bioenergetic Modulators against Protozoan Parasites Responsible for Tropical Diseases","volume":"14","author":"Galizzi","year":"2020","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"doi-asserted-by":"crossref","unstructured":"Li, Y.-Q., Zheng, Z., Liu, Q.-X., Lu, X., Zhou, D., Zhang, J., Zheng, H., and Dai, J.-G. (2021). Repositioning of Antiparasitic Drugs for Tumor Treatment. Front. Oncol., 11.","key":"ref_37","DOI":"10.3389\/fonc.2021.670804"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1002\/cmdc.202000331","article-title":"Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma Cruzi and Plasmodium falciparum","volume":"15","author":"Gomes","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"116796","DOI":"10.1016\/j.ejmech.2024.116796","article-title":"Discovery of 1,3,4-Oxadiazoles with Slow-Action Activity against Plasmodium falciparum Malaria Parasites","volume":"278","author":"Andrews","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e202401366","DOI":"10.1002\/asia.202401366","article-title":"Design, Synthesis and in Vitro Evaluation of Primaquine and Diaminoquinazoline Hybrid Molecules Against the Malaria Parasite","volume":"20","author":"Kore","year":"2025","journal-title":"Chem.\u2013Asian J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10534-022-00375-8","article-title":"Synthesis and Antimalarial Activity of Amide and Ester Conjugates of Siderophores and Ozonides","volume":"36","author":"Tiwari","year":"2023","journal-title":"BioMetals"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nrd4683","article-title":"Hit and Lead Criteria in Drug Discovery for Infectious Diseases of the Developing World","volume":"14","author":"Katsuno","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1128\/AAC.48.6.2116-2123.2004","article-title":"Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum","volume":"48","author":"Gatton","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S1471-4922(01)02085-2","article-title":"Pyrimethamine\u2013Sulfadoxine Resistance in Plasmodium falciparum: What Next?","volume":"17","author":"Sibley","year":"2001","journal-title":"Trends Parasitol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12025","DOI":"10.1073\/pnas.0905922106","article-title":"Stepwise Acquisition of Pyrimethamine Resistance in the Malaria Parasite","volume":"106","author":"Lozovsky","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"doi-asserted-by":"crossref","unstructured":"Amusengeri, A., Tata, R.B., and Tastan Bishop, \u00d6. (2020). Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis. Molecules, 25.","key":"ref_46","DOI":"10.3390\/molecules25040904"},{"doi-asserted-by":"crossref","unstructured":"Ahmadi, A., Mohammadnejadi, E., and Razzaghi-Asl, N. (2023). Gefitinib Derivatives and Drug-Resistance: A Perspective from Molecular Dynamics Simulations. Comput. Biol. Med., 163.","key":"ref_47","DOI":"10.1016\/j.compbiomed.2023.107204"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1007\/s11434-010-3257-6","article-title":"Molecular Dynamics Simulations Exploring Drug Resistance in HIV-1 Proteases","volume":"55","author":"Gu","year":"2010","journal-title":"Chin. Sci. Bull."},{"key":"ref_49","first-page":"1033","article-title":"Insights on Microsomal Prostaglandin E2 Synthase 1 (MPGES-1) Inhibitors Using Molecular Dynamics and MM\/PBSA Calculations","volume":"21","year":"2023","journal-title":"Lett. Drug Des. Discov."},{"doi-asserted-by":"crossref","unstructured":"Albino, S.L., da Silva Moura, W.C., dos Reis, M.M.L., Sousa, G.L.S., da Silva, P.R., de Oliveira, M.G.C., Borges, T.K.d.S., Albuquerque, L.F.F., de Almeida, S.M.V., and de Lima, M.d.C.A. (2023). ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation. Pharmaceuticals, 16.","key":"ref_50","DOI":"10.3390\/ph16020204"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2174\/1570180819666220106110133","article-title":"Repurposing FDA-Approved Drugs Targeting SARS-CoV2 3CLpro: A Study by Applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking","volume":"19","author":"Nascimento","year":"2022","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2174\/0115734099274797231205055827","article-title":"Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain Using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations","volume":"21","author":"Nascimento","year":"2024","journal-title":"Curr. Comput.-Aided Drug Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/S0020-7519(97)00080-5","article-title":"Continuous Culture of Plasmodium falciparum: Its Impact on Malaria Research","volume":"27","author":"Trager","year":"1997","journal-title":"Int. J. Parasitol."},{"doi-asserted-by":"crossref","unstructured":"de Sousa, N.F., de Freitas, M.E.G., Sidr\u00f4nio, M.G.S., Souza, H.D., Czeczot, A., Perell\u00f3, M., Fiss, G.F., Scotti, L., de Ara\u00fajo, D.A.M., and Barbosa Filho, J.M. (2025). Preclinical Evaluation of Selene-Ethylenelacticamides in Tuberculosis: Effects Against Active, Dormant, and Resistant Mycobacterium tuberculosis and in Vitro Toxicity Investigation. Microorganisms, 13.","key":"ref_55","DOI":"10.3390\/microorganisms13020396"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/wcms.81","article-title":"The ORCA Program System","volume":"2","author":"Neese","year":"2012","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e1606","DOI":"10.1002\/wcms.1606","article-title":"Software Update: The ORCA Program System\u2014Version 5.0","volume":"12","author":"Neese","year":"2022","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/wcms.1161","article-title":"Semiempirical Quantum-Chemical Methods","volume":"4","author":"Thiel","year":"2014","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and Validation of a Genetic Algorithm for Flexible Docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_60","first-page":"2317","article-title":"TNF-\u03b1 Inhibitors from Natural Compounds: An Overview, CADD Approaches, and Their Exploration for Anti-Inflammatory Agents","volume":"25","year":"2021","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2174\/2772270816666220126103909","article-title":"Molecular Docking and Dynamics Simulations Studies of a Dataset of NLRP3 Inflammasome Inhibitors","volume":"15","year":"2022","journal-title":"Recent Adv. Inflamm. Allergy Drug Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL Workspace: A Web-Based Environment for Protein Structure Homology Modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/jcc.21816","article-title":"SwissParam: A Fast Force Field Generation Tool for Small Organic Molecules","volume":"32","author":"Zoete","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.crtox.2021.11.002","article-title":"The New Psychoactive Substances 25H-NBOMe and 25H-NBOH Induce Abnormal Development in the Zebrafish Embryo and Interact in the DNA Major Groove","volume":"2","author":"Nunes","year":"2021","journal-title":"Curr. Res. Toxicol."},{"doi-asserted-by":"crossref","unstructured":"Silva, L.R., Guimar\u00e3es, A.S., do Nascimento, J., do Santos Nascimento, I.J., da Silva, E.B., McKerrow, J.H., Cardoso, S.H., and da Silva-J\u00fanior, E.F. (2021). Computer-Aided Design of 1,4-Naphthoquinone-Based Inhibitors Targeting Cruzain and Rhodesain Cysteine Proteases. Bioorg. Med. Chem., 41.","key":"ref_65","DOI":"10.1016\/j.bmc.2021.116213"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"G_mmpbsa\u2014A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"doi-asserted-by":"crossref","unstructured":"Nascimento, I.J.d.S., Mendon\u00e7a de Aquino, T., and Ferreira da Silva-J\u00fanior, E. (2022). Molecular Dynamics Applied to Discover Antiviral Agents. Frontiers in Computational Chemistry, Bentham Science.","key":"ref_67","DOI":"10.2174\/9789815036848122060005"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/12\/1214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T05:13:42Z","timestamp":1764825222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/12\/1214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":67,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["antibiotics14121214"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics14121214","relation":{},"ISSN":["2079-6382"],"issn-type":[{"type":"electronic","value":"2079-6382"}],"subject":[],"published":{"date-parts":[[2025,12,2]]}}}