Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers |
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| Affiliation: | 1. Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea;2. Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;3. Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, Canada;4. KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, 11795 Helwan, Cairo, Egypt;2. Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia;3. Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;5. Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza 12622, Egypt;6. Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt;7. Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University, 12451, Sixth of October City, Giza, Egypt;8. Radioactive Isotopes and Generators Department, Hot Laboratories Centre, Atomic Energy Authority, P.O. Code 13759 Cairo, Egypt;1. Department of Radiation Oncology, Emory University School of Medicine, USA;2. Department of Radiology and Image Sciences, Emory University School of Medicine, USA;3. Winship Cancer Institute, Atlanta, GA 30322, USA;1. Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Chung Buk, 28119, Republic of Korea;2. Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongju, 28116, Republic of Korea;3. Department of Biomedical Science, Graduate School, Cellular and Molecular Medicine, Chosun University, Gwangju, 61452, Republic of Korea;4. Department of Bio-analytical Science, University of Science & Technology, Daejeon, 34113, Republic of Korea;1. Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG, Universidade Federal do Rio de Janeiro, CEP 21949-900 Rio de Janeiro, RJ, Brazil;2. Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP 13560-970 São Carlos, SP, Brazil;3. Departamento de Virologia, IMPG, Universidade Federal do Rio de Janeiro, CEP 21949-900 Rio de Janeiro, RJ, Brazil;1. Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;2. Laboratory of Natural Product, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;3. Advanced Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan;4. Division of Chemistry and Materials, Graduate School of Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan |
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| Abstract: | In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivatives using an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Cav3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC50 values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels. |
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| Keywords: | 2-thio-3,4-dihydroquinazoline Current inhibition Cytotoxicity |
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