Structure–Activity Relationship Studies of Acetazolamide-Based Carbonic Anhydrase Inhibitors with Activity against Neisseria gonorrhoeae
- Chad S. HewittChad S. HewittDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Chad S. Hewitt
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- Nader S. AbutalebNader S. AbutalebDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United StatesMore by Nader S. Abutaleb
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- Ahmed E. M. ElhassannyAhmed E. M. ElhassannyDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United StatesMore by Ahmed E. M. Elhassanny
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- Alessio NocentiniAlessio NocentiniDepartment of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze 50122, ItalyMore by Alessio Nocentini
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- Xufeng CaoXufeng CaoDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Xufeng Cao
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- Devon P. AmosDevon P. AmosDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Devon P. Amos
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- Molly S. YouseMolly S. YouseDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Molly S. Youse
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- Katrina J. HollyKatrina J. HollyDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Katrina J. Holly
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- Anil Kumar MarapakaAnil Kumar MarapakaDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Anil Kumar Marapaka
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- Weiwei AnWeiwei AnDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Weiwei An
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- Jatinder KaurJatinder KaurDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Jatinder Kaur
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- Aaron D. KrabillAaron D. KrabillDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Aaron D. Krabill
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- Ahmed ElkashifAhmed ElkashifDepartment of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, United StatesMore by Ahmed Elkashif
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- Yehia ElgammalYehia ElgammalDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United StatesMore by Yehia Elgammal
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- Amanda L. GraboskiAmanda L. GraboskiDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesMore by Amanda L. Graboski
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- Claudiu T. SupuranClaudiu T. SupuranDepartment of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze 50122, ItalyMore by Claudiu T. Supuran
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- Mohamed N. Seleem*Mohamed N. Seleem*Email: [email protected]Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United StatesMore by Mohamed N. Seleem
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- Daniel P. Flaherty*Daniel P. Flaherty*Email: [email protected]Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United StatesPurdue Institute for Drug Discovery, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesPurdue Institute of Inflammation, Immunology and Infectious Disease, 207 South Martin Jischke Drive, West Lafayette, Indiana 47907, United StatesMore by Daniel P. Flaherty
Abstract
Neisseria gonorrhoeae is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat N. gonorrhoeae infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria’s essential carbonic anhydrase, NgCA. This study established both structure–activity and structure–property relationships that contribute to both antimicrobial activity and NgCA activity. This ultimately led to molecules 20 and 23, which displayed minimum inhibitory concentration values as low as 0.25 μg/mL equating to an 8- to 16-fold improvement in antigonococcal activity compared to acetazolamide. These analogues were determined to be bacteriostatic against the pathogen and likely on-target against NgCA. Additionally, they did not exhibit any detrimental effects in cellular toxicity assays against both a human endocervical (End1/E6E7) cell line or colorectal adenocarcinoma cell line (Caco-2) at concentrations up to 128 μg/mL. Taken together, this study presents a class of antigonococcal agents with the potential to be advanced for further evaluation in N. gonorrhoeae infection models.
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