New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis

Abstract

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL−1). These compounds offer good opportunities as leads for further optimisation.

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

“…InhA has an active site where catalytic residues Lys165 and Tyr158 are located in the substrate-binding pocket interacting with the long-chain fatty acyl substrates required for the synthesis of mycolic acid ( 75 , 78 ). INH is a prodrug that is oxidized by KatG creating the INH-NAD adduct, a competent InhA inhibitor ( 76 ).…”

Triclosan: A Small Molecule with Controversial Roles

“…It inhibits blood-stage Plasmodium , via its action against dihydrofolate reductase, and the liver stage of the parasite, via the inhibition of ENR [ 85 ]. Several recent studies are aimed at obtaining new analogs of TCS that are more active and less toxic than the parent compound [ 86 , 87 ].…”

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

“…In order to generate analogs which overcome resistance, the development of direct InhA inhibitors which do not require activation shows promise. Early work on triclosan and its derivatives confirmed that it was possible to develop alternative inhibitors for InhA (Armstrong et al, 2020;Rodriguez et al, 2020;Chetty et al, 2021) and multiple scaffolds, as well as a natural product, have been identified which can inhibit InhA (Pan and Tonge, 2012). These newer analogs generally do not require activation and bind directly to InhA, thus they can overcome resistance due to KatG and InhA mutation.…”