Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors

Abstract

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 ( K D ). 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, K D 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 Å 3 , topological polar surface area <40 Å 2 .

Chemical Composition and Immunomodulatory Activity of Hypericum perforatum Essential Oils

“…Nevertheless, they differed noticeably in topological polar surface area (tPSA) and Log P. These descriptors are usually related to the capacity of molecules to cross cellular membranes [ 82 ]. For example, it was reported earlier that compounds with LogP > 4 and TPSA < 40 Å 2 had optimal antimycobacterial activity [ 83 ]. Thus, it is possible that the inactivity of β-caryophyllene oxide in human neutrophils could be explained by low cell membrane permeability, as this compound is less lipophilic and more polar than the investigated sesquiterpenes of purely hydrocarbon nature.…”

19F-NMR reveals substrate specificity of CYP121A1 in Mycobacterium tuberculosis

“…CYP121A1 mediates a rare phenol-coupling reaction of the dipeptide dicyclotyrosine (cYY) to produce mycocyclosin, a product of undetermined function ( 13 ). Despite this, inhibition of CYP121A1 remains a potential strategy in the treatment of TB and multidrug-resistant forms of the disease ( 14 , 15 , 16 ).…”

A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)

“…As the substrate for the enzyme (cYY) has a cLogP of 0.82, the enzyme is clearly designed to accommodate substrate and product that are highly hydrophilic in nature. Recent studies recording imidazolyl- and triazolyl-derived pyrazoles as inhibitors of CYP121A1 have shown that, whilst compounds with higher lipophilicity (cLogP >4) showed better activity in cellulo , only some of those with much lower cLogP (1.44 and 2.68) afforded useable crystal structures [ 22 ]. These opposing factors clearly constitute a significant challenge in this area, as compounds that deliver the greatest structural knowledge struggle to permeate the highly lipophilic mycolic acid derived cell wall of Mtb and so invariably show much lower in cellulo potencies.…”