10779/crick.11559861.v1
Safaa M Kishk
Safaa M
Kishk
Kirsty J McLean
Kirsty J
McLean
Sakshi Sood
Sakshi
Sood
Darren Smith
Darren
Smith
Jack WD Evans
Jack WD
Evans
Mohamed A Helal
Mohamed A
Helal
Mohamed S Gomaa
Mohamed S
Gomaa
Ismail Salama
Ismail
Salama
Samia M Mostafa
Samia M
Mostafa
Luiz Pedro S de Carvalho
Luiz Pedro S
de Carvalho
Colin W Levy
Colin W
Levy
Andrew W Munro
Andrew W
Munro
Claire Simons
Claire
Simons
Design and synthesis of imidazole and triazole pyrazoles
as Mycobacterium tuberculosis CYP121A1 inhibitors.
The Francis Crick Institute
2020
Binding affinity
Imidazole derivatives
X-ray crystallography
molecular modelling
mycobacterium tuberculosis
Carvalho FC001060
0302 Inorganic Chemistry
0305 Organic Chemistry
0306 Physical Chemistry (incl. Structural)
2020-01-09 16:45:23
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Design_and_synthesis_of_imidazole_and_triazole_pyrazoles_as_Mycobacterium_tuberculosis_CYP121A1_inhibitors_/11559861
The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 Å3, topological polar surface area <40 Å2.