Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents |
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| Institution: | 1. School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa;2. Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA;1. Department of Ultrasound Diagnosis, Xijing Hospital, Fourth Military Medical University, Xi''an 710038, China;2. Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China;1. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India;2. Institut de Recherche en Infectiologie (IRIM) de Montpellier, CNRS, UMR 9004 Université de Montpellier, France;3. INSERM, IRIM, 34293 Montpellier, France;4. School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa;1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China;2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China;1. Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, 522 510, Andhra Pradesh, India;2. Department of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Sri Ramachandra Nagar, Porur, Chennai, 600116, Tamil Nadu, India;3. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835 215, India;4. Medicinal Chemistry and Pharmacology Division, CSIR – Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500 007, Telangana, India;1. Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University SubCampus, Osmanabad 413 501, MS, India;2. Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, MS, India;3. Department of Microbiology, Dr. Babasaheb Ambedkar Marathwada University SubCampus, Osmanabad 413 501, MS, India;4. Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, R. R. District, Hyderabad 500078, India;5. Department of Pharmaceutical Chemistry, School of Pharmacy, Vishwakarma University, Pune 411 048, MS, India;1. Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan;2. Whol Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 7610001, Israel;3. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel |
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| Abstract: | New indole-tethered 1,3,4]thiadiazolo3,2-a]pyrimidin-5-one (8a-j) and 1,3,4]oxadiazolo3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using 4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The 1,3,4]oxadiazolo3,2-a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity than the 1,3,4]thiadiazolo3,2-a]pyrimidin-5-one hybrids (8a-j) against the PANC-1 cell line. Compound 9d bearing an ortho-chlorophenyl moiety emerged as the most potent anti-pancreatic cancer agent with an IC50 value of 7.7 ± 0.4 µM, much superior to the standard drug Gemcitabine (IC50 > 500 µM). The discovery of these 1,3,4]thiadiazolo and 1,3,4]oxadiazolo3,2-a]pyrimidin-5-one hybrids elicits their potentials as pursuable candidates for pancreatic cancer chemotherapy. |
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| Keywords: | [4+2] Cycloaddition reaction Pyrimidinone Indole Molecular hybridization Pancreatic cancer |
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