Abstract
The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a CC crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25 μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KD = 1.6 μM; tBu KD = 1.2 μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.
Highlights
Tuberculosis (TB) is the ninth leading cause of death worldwide, ranking above Human Immunodeficiency Virus (HIV/AIDS)
Long treatment durations are usually required because Mycobacterium tuberculosis (Mtb), the causative pathogen, can develop a dormancy phenotype under nutrient depletion and anaerobiosis conditions which is tolerant to several anti-TB drugs.[6,7]
In the development of CYP121A1 inhibitors, we have described several series of compounds with chemical scaffolds that mimic the natural substrate crosslinking reaction of dicyclotyrosine (cYY).[18,19]
Summary
Tuberculosis (TB) is the ninth leading cause of death worldwide, ranking above Human Immunodeficiency Virus (HIV/AIDS). The duration for treating drug-sensitive TB is usually 6 months with the four most effective agents from the first-line oral drugs administered in a single prescription for the first two months of treatment, and two of the four taken for a subsequent four months in the continuation phase, resulting in patient adherence issues.[5] When administered in sub-optimum conditions, chronic cases of infectious drug-resistant TB appear. Long treatment durations are usually required because Mycobacterium tuberculosis (Mtb), the causative pathogen, can develop a dormancy phenotype under nutrient depletion and anaerobiosis conditions which is tolerant to several anti-TB drugs.[6,7] The development of novel anti-TB drugs has become a priority in view of the increasing global incidence of strains resistant to at least rifampicin and isoniazid (MDR-TB), or to rifampicin, isoniazid and one of the injectable second-line anti-TB drugs as well as to any of the fluoroquinolone drug series (XDR-TB),[1] in addition to the interactions between anti-TB drugs and antiretroviral medications, and the need to treat latent TB-infected patients before the bacteria transform into their active form.[8]
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