Design, Synthesis, and Evaluation of Novel Antimycobacterial Agents With Enhanced Pharmacokinetic Profiles
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Authors
Bhattarai, Pankaj
Issue Date
2019-07-18
Volume
Issue
Type
Dissertation
Language
en_US
Keywords
Alternative Title
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), is one of the leading causes of death worldwide. The present short-course therapy is six months long for drug-susceptible M. tb strains, and up to two years for multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) due to a lack of effective treatment. Non-tuberculous mycobacteria (NTM) such as the M. avium and M. abscessus complexes (MAC and MABSC, respectively) are opportunistic pathogens found ubiquitously in the environment. NTM infections have increasing prevalence in patients with structural lung diseases, including chronic obstructive pulmonary disease and cystic fibrosis. Current treatment recommendations for MAC and MABSC infections last for at least 12 months and include multidrug therapy with combinations of intravenous and oral antibiotics. The long-combined therapy is accompanied with many adverse effects and is routinely ineffective. Therefore, novel anti-TB and -NTM agents with greater efficacy and shorter treatment times are the need of the hour.
One of the common drug targets for antibiotic intervention is the inhibition of bacterial cell wall biosynthesis. Mycolic acids, which are α-alkylated β-hydroxylated fatty acids, are the primary lipid constituents of the mycobacterial cell wall and are synthesized intracellularly in the cytoplasm. Mycobacterial membrane protein large 3 (MmpL3) is an essential transporter protein that translocates mycolic acids as trehalose monomycolates (TMM), an ester comprising trehalose sugar and a mycolic acid, across the plasma membrane. The inhibition of this novel target obstructs the TMM transport, disrupting the cell wall assembly, leading to the inhibition of cell growth. Our group has previously developed urea- and indole-based compounds that are putative MmpL3 inhibitors with high activity at concentrations of sub-µg/mL against a panel of mycobacteria. However, they have poor aqueous solubility limiting their translational potential. Our efforts to improve the aqueous solubility of the indole-based compounds has yielded the acetamide series. The design is based on the hypothesis that ‘Medicinal chemistry ligand-based optimization of the indole series to generate the acetamide series maintains the pharmacophore while decreasing the percentage of lipophilic carbon atoms, thus retaining potent antimycobacterial activity and increasing aqueous solubility.’ Minimum inhibitory concentration values against a panel of mycobacteria, including M. abscessus and M. tuberculosis were assessed along with in vitro cytotoxicity profiles, pharmacokinetic and physicochemical parameters, including aqueous solubility, permeability, and human plasma protein binding. Based on the preliminary data, of the 39 compounds tested, compounds 192 and 200 were identified as the best leads, with potent activity against both M. tb and M. abscessus strains and 20- to 30-fold improvement in aqueous solubility compared to indoles, while maintaining optimal ADME-Tox.
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Citation
Publisher
Creighton University
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Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.