The alarming rise in drug-resistant clinical cases of tuberculosis (TB) has necessitated the rapid development of newer chemotherapeutic agents with novel mechanisms of action. The mycobactin biosynthesis pathway, conserved only among the mycolata family of actinobacteria, a group of intracellularly surviving bacterial pathogens that includes Mycobacterium tuberculosis, generates a salicyl-capped peptide mycobactin under ironstress conditions in host macrophages to support the iron demands of the pathogen. This in vivo essentiality makes this less explored mycobactin biosynthesis pathway a promising endogenous target for novel lead-compounds discovery. In this Perspective, we have provided an up-to-date account of drug discovery efforts targeting selected enzymes (MbtI, MbtA, MbtM, and PPTase) from the mbt gene cluster (mbtA-mbtN). Furthermore, a succinct discussion on non-specific mycobactin biosynthesis inhibitors and the Trojan horse approach adopted to impair iron metabolism in mycobacteria has also been included in this Perspective.
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.
Borax efficiently catalysed the synthesis of a series of spirooxindole and chromeno [2, 3-b]pyridine-3-carbonitrile derivatives in domino fashion via Knoevenagel condensation followed by Michael addition. This synthetic scheme is operationally simple, affording excellent yield and can be considered as an approach towards 'green chemistry'. In-silico docking studies of the synthesized molecules were carried to investigate the antitumor activity and to predict its binding affinity and orientation at the active site of human anaplastic lymphoma protein (Protein Data Bank (PDB): 2xp2). Molecular docking studies indicated that 2-amino-5'-chloro-7,7-dimethyl-2',5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4, 3'-indoline]-3-carbonitrile (1 e) and 2 '-amino-5-chloro-2,5'-dioxo-5'H-spiro[indoline-3, 4'pyrano[3, 2-c]chromene]-3'-carbonitrile (2 b) appeared to show strong interactions at the receptor active site with predicted binding energy of À 8.47 kcal/mol and À 9.19 kcal/mol respectively. A detailed analysis of topology of the compounds 1 e and 2 b were also determined by X-ray crystallography and Hirshfeld surface analysis to get an insight of the packing and intermolecular interactions in their molecular structure.
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Iron overload disorder and diseases where iron mismanagement plays a crucial role require
orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin
(DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its
use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT
has been naturally well optimized for better iron chelation and iron clearance from human biological
system. Equally they are also responsible for its toxicity. Hence, subsequent research has been devoted
to develop a non-nephrotoxic analogue of DFT without losing its iron clearance ability.
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The review has been designed to classify the compounds reported till date and to discuss the structure
activity relationship with reference to modifications attempted at different positions over pyridine and
thiazoline ring of DFT. Compounds are clustered under two major classes: (i) Pyridine analogues and
(ii) phenyl analogue and further each class has been further subdivided based on the presence or absence
and the number of hydroxy functional groups present over pyridine or phenyl ring of the DFT
analogues. Finally a summary and few insights into the development of newer analogues are provided.
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