title: Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies.
abstract: A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents.
authors.affiliation: Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand. Electronic address: ratchanok@swu.ac.th.
authors.forename: Ratchanok
authors.initials: R
authors.lastname: Pingaew
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Veda
authors.initials: V
authors.lastname: Prachayasittikul
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Apilak
authors.initials: A
authors.lastname: Worachartcheewan
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Chanin
authors.initials: C
authors.lastname: Nantasenamat
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Supaluk
authors.initials: S
authors.lastname: Prachayasittikul
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, and Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand. Electronic address: virapong.pra@mahidol.ac.th.
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D009285:Naphthoquinones; D013449:Sulfonamides; C035342:1,4-naphthoquinone
keywords: Anticancer activity; Antimalarial activity; Naphthoquinone; QSAR; Sulfonamide