Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition

Abstract

In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds 44 and 49 as potential mycobactin biosynthesis inhibitors against mycobacteria. Moreover, candidates efficiently eradicated intracellularly surviving mycobacteria. Thermofluorimetric analysis and molecular dynamics simulations suggested that compounds 44 and 49 bind to salicyl-AMP ligase (MbtA), a key enzyme in the mycobactin biosynthetic pathway. To the best of our knowledge, these are the first rationally designed mycobactin inhibitors to demonstrate an excellent in vivo pharmacokinetic profile. In addition, these compounds also exhibited more potent whole-cell efflux pump inhibition than known efflux pump inhibitors verapamil and chlorpromazine. Results from this study pave the way for the development of 3-(2-hydroxyphenyl)-5-(aryl)-pyrazolines as a new weapon against superbug-associated AMR challenges.

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

“…Therefore, there is a growing interest in targeting the pathways involved in its acquisition [ 34 , 35 , 36 ]. In detail, the production of siderophores (mycobactins and carboxymycobactins) has been shown to be of crucial importance; hence, proteins involved in their assembly, transport, and functionality have been proposed as potential targets [ 37 , 38 , 39 , 40 , 41 , 42 ]. Moreover, siderophores have been shown to prevent phagosome maturation inside macrophages and induce hypoxia-like toxicity in host cells [ 7 , 43 ].…”

Antioxidant activity of novel nitrogen scaffold with docking investigation and correlation of DFT stimulation

“…We examined the reactivity of chalcone 1 towards aza-Michael addition reactions using different nitrogen-attacking nucleophiles (Michael donors) such as hydrazine hydrate, phenyl hydrazine derivatives, hydroxylamine, guanidine, urea, thiourea, and heterocyclic amines to form different heterocyclic active compounds. Different pyrazolines 3 and 4 were formed under microwave radiation from the reaction of chalcone 1 with hydrazine hydrate 2 in different solvents such as ethanol and acetic acid as the reported method 42,43 (Scheme 1). The IR spectrum of compound 3 showed characteristic stretching bands at 3339, 3006, and 1619 cm −1 due to NH, aromatic C-H, and C]N groups, respectively.…”

“…White crystals was formed aer cooling and ltered. Yield (0.8 g, 76%), M p 106 °C (literature: 65 (CH 2 ), 61.10 (CH), 111.86 (C) 13 (11). A mixture of compound 1 (1.0 g, 4.2 mmol), guanidine (0.4 g, 4.2 mmol) and KOH (0.47 g, 8.4 mmol) was dissolved in EtOH (8 mL) and irradiated at 70 °C for 1.5 h using microwave.…”

TargetingMycobacterium tuberculosisiron-scavenging tools: a recent update on siderophores inhibitors

“…Interestingly, 86 and 87 demonstrated efflux pump inhibition in M. smegmatis, highlighting their potential in reversing drug resistance. 235 Rakshit et al designed a 12-member small library of mycobactin analogues retaining the diaryl-substituted pyrazoline as the primary scaffold. The docking of the designed molecules was performed in the active site of the MbtA receptor (by analogy with the related structure, PDB: 1MDB) to evaluate the binding modes and inhibitory profiles.…”

“…Interestingly, 86 and 87 demonstrated efflux pump inhibition in M. smegmatis , highlighting their potential in reversing drug resistance. 235…”