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Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).
Hegde, Pooja V; Howe, Michael D; Zimmerman, Matthew D; Boshoff, Helena I M; Sharma, Sachin; Remache, Brianna; Jia, Ziyi; Pan, Yan; Baughn, Anthony D; Dartois, Veronique; Aldrich, Courtney C.
Afiliação
  • Hegde PV; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
  • Howe MD; Department of Microbiology & Immunology, University of Minnesota, Minneapolis, MN, USA.
  • Zimmerman MD; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • Boshoff HIM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
  • Sharma S; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
  • Remache B; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • Jia Z; Department of Microbiology & Immunology, University of Minnesota, Minneapolis, MN, USA.
  • Pan Y; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • Baughn AD; Department of Microbiology & Immunology, University of Minnesota, Minneapolis, MN, USA.
  • Dartois V; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • Aldrich CC; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA. Electronic address: aldri015@umn.edu.
Eur J Med Chem ; 232: 114201, 2022 Mar 15.
Article em En | MEDLINE | ID: mdl-35219151
Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácido Aminossalicílico / Tuberculose / Pró-Fármacos / Tuberculose Resistente a Múltiplos Medicamentos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácido Aminossalicílico / Tuberculose / Pró-Fármacos / Tuberculose Resistente a Múltiplos Medicamentos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article