Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1.
Bioorg Med Chem
; 27(8): 1546-1561, 2019 04 15.
Article
em En
| MEDLINE
| ID: mdl-30837169
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⯵g/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KDâ¯=â¯1.6⯵M; tBu KDâ¯=â¯1.2⯵M). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Cíclicos
/
Sistema Enzimático do Citocromo P-450
/
Dipeptídeos
/
Mycobacterium tuberculosis
/
Antituberculosos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2019
Tipo de documento:
Article