Developing pyrazole-oxadiazole conjugates as potent anti-tubercular agents: an in
silico and in vitro approach
#MMPMID41384053
Kumar SA
; Besra G
; Batt S
; Chandrashekar VM
; Singh M
; Akshatha HS
; Bhagyalalitha M
; Pujar KG
; Bidye D
; Madhukumari
; Pujar GV
RSC Med Chem
2025[Dec]; ? (?): ? PMID41384053
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Decaprenylphosphoryl-beta-d-ribose 2'-oxidase (DprE1) is a unique enzyme in
Mycobacterium tuberculosis (Mtb) essential for the synthesis of the cell wall
constituent arabinan. It converts decaprenyl phosphoryl ribose (DPR) to
decaprenyl phosphoryl arabinose (DPA) with DprE2. Inhibition of DprE1 affects the
integrity of the cellular membrane, causing cell wall rupture, leakage of
cellular contents, and ultimately, cell death. Structural analysis of the DprE1
binding site reveals three binding regions: hydrophobic head region, planar core
nucleus, and solvent-accessible tail region. Based on these structural features
and reported inhibitors, structure-based drug design (SBDD) was employed to
design and develop 22 novel pyrazole-oxadiazole conjugates (PO1-PO22), combining
a hydrophobic pyrazole and planar oxadiazole connected to an amide linker. The
designed compounds were synthesized and evaluated for antitubercular activity
against the Mtb H37Rv strain using the Microplate Alamar Blue (MAB) assay. Among
them, PO3 and PO4 exhibited potent activity with MIC values of 0.24 and 0.53 ?M,
respectively, better than the known DprE1 inhibitor TCA-1 (MIC 0.66 ?M). Six
compounds with MICs < 2.5 ?M were further screened for DprE1 inhibition. PO3 and
PO4 showed IC(50) values of 32.7 ± 6.0 and 39.2 ± 7.3 ?M, suggesting DprE1 may
not be their primary target. Molecular dynamics simulations (200 ns) supported
the limited stability of DprE1-ligand complexes. Notably, the active compounds
displayed excellent safety (IC(50) > 500 ?M) in NIH/3T3 fibroblast cytotoxicity
assays. Overall, the pyrazole-oxadiazole conjugates represent promising anti-Mtb
agents, likely acting through multi-target mechanisms within the pathogen.
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