TY - JOUR
T1 - Structural Determinants of Indole-2-carboxamides
T2 - Identification of Lead Acetamides with Pan Antimycobacterial Activity
AU - Bhattarai, Pankaj
AU - Hegde, Pooja
AU - Li, Wei
AU - Prathipati, Pavan Kumar
AU - Stevens, Casey M.
AU - Yang, Lixinhao
AU - Zhou, Hinman
AU - Pandya, Amit
AU - Cunningham, Katie
AU - Grissom, Jenny
AU - Roman Sotelo, Mariaelena
AU - Sowards, Melanie
AU - Calisto, Lilian
AU - Destache, Christopher J.
AU - Rocha-Sanchez, Sonia
AU - Gumbart, James C.
AU - Zgurskaya, Helen I.
AU - Jackson, Mary
AU - North, E. Jeffrey
N1 - Funding Information:
Research reported in this publication was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases research grant AI116525, the Translational Hearing Center Creighton University Center of Biomedical Research Excellence (COBRE) of the National Institutes of Health under grant number 1P20GM139762-01, the Health Science Strategic Investment Fund Faculty Development Grant, the Cystic Fibrosis Foundation (NORTH18I0), and the Jack and Lois Wareham Research Award. The authors would also like to thank the Department of Chemistry at Creighton University for the use of their NMR and Dr. William Jacobs (Albert Einstein College of Medicine, NY, USA) for the provision of M. tuberculosis H37Rv mc 6206. 2
Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/1/12
Y1 - 2023/1/12
N2 - Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.
AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.
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U2 - 10.1021/acs.jmedchem.2c00352
DO - 10.1021/acs.jmedchem.2c00352
M3 - Article
C2 - 36563291
AN - SCOPUS:85146192949
SN - 0022-2623
VL - 66
SP - 170
EP - 187
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -