Scaffold-switching: An exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA;2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;3. Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA;1. Dipartimento di Farmacia, Università di Napoli ‘Federico II’, Via D. Montesano 49, 80131 Napoli, Italy;2. Key Laboratory for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China;4. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Via Pascal 36, I-20133 Milano, Italy;5. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via Pascal 36, I-20133 Milano, Italy;1. Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic;2. Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, Pardubice 532 10, Czech Republic;3. Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic;4. Institute of Organic Chemistry and Biochemistry v.v.i and Gilead Sciences and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic;5. Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Palacký University, Olomouc, 771 46 Olomouc, Czech Republic;1. Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia;2. Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia;3. Department of Animal Husbandry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia;1. Université de Nantes, Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, F-44000, Nantes, France;2. BioCIS Biomolécules: Conception, Isolement, Synthèse, Chimiothérapie Antiparasitaire, UMR CNRS 8076, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, F-92296, Châtenay-Malabry, France;3. Institut Pasteur and Institut National de Santé et Recherche Médicale INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, F-75015, Paris, France;4. Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, F-29680, Roscoff, France;5. Sorbonne Université, CNRS, FR2424, Kinase Inhibitor Specialized Screening Facility - KISSf, Station Biologique, F-29680, Roscoff, France |
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| Abstract: | A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a homologous imidazo[1,2-a]pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H37Rv Mtb (MIC’s of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM). |
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| Keywords: | Antituberculosis 5,6-Fused bicyclic system Scaffold hopping |
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