Novel Potent Imidazo[1,2-a]pyridine-N-Glycinyl-Hydrazone Inhibitors of TNF-α Production: In Vitro and In Vivo Studies

Abstract

In this work, we describe the design, synthesis and pharmacological evaluation of novel imidazo[1,2-a]pyridine-N-glycinyl-hydrazone derivatives (1a–k) intended for use as inhibitors of tumor necrosis factor alpha (TNF-α) production. The compounds were designed based on the orally active anti-inflammatory prototype LASSBio-1504 (2), which decreases the levels of the pro-inflammatory cytokine TNF-α in vitro and in vivo. The in vitro pharmacological evaluation of the imidazo[1,2-a]pyridine compounds (1) showed that substitution of the N-phenylpyrazole core present in prototype 2 by a bioisosteric imidazo[1,2-a]pyridine scaffold generated anti-TNF-α compounds that were more potent than the previously described N-phenylpyrazole derivative 2 and as potent as SB-203580, a p38 MAPK inhibitor. The most active derivative (E)-2-(2-tert-butylimidazo[1,2-a]pyridin-3-ylamino)-N’-(4-chlorobenzylidene) acetohydrazide, or LASSBio-1749 (1i) was orally active as an anti-inflammatory agent in a subcutaneous air pouch model, reducing expressively the levels in vivo of TNF-α and other pro-inflammatory cytokines at all of the tested doses.

The Groebke‐Blackburn‐Bienaymé Reaction

“…Overview of GBB catalysts that performed best in reported catalyst screenings (single hits were omitted for clarification). TiO 2 NPs (nanopowders) [170] TMSCl 7 [37,38,53,152,155,169,176] ZnO NPs [116] Montmorillonite K-10 clay 6 [19,64,65,70,121,192] Methanesulfonic acid [52] Magnesium chloride (MgCl 2 ) 5 [134,136,193,194] Zeolite HY [195] Ytterbium triflate (Yb(OTf) 3 ) 4 HCl dioxane 4 [72,73,84,117] Bromodimethylsulfonium bromide (BDMS) [69] Indium triflate (In(OTf) 3 ) 3 [108,109,122] γ-Fe 2 O 3 @SiO 2 -OSO 3 H [71] Trifluoroacetic acid (TFA) 2 [82,165] Cationic polyurethane dispersions (CPUDs) [76] Bismuth chloride (BiCl 3 ) 2 [81,91] pTsCl [77] Silica sulfuric acid 2 [126,148] Iodine [135] Lanthanum chloride (LaCl 3 •7H 2 O) 2 [92,104] (TBBDA) [83] Piperidine 2 [162,163] (PBBS)…”

Groebke–Blackburn–Bienaymé multicomponent reaction: emerging chemistry for drug discovery

“…Very recently, Lacerda and colleagues [82] reported the synthesis of novel potent imidazo[1,2-a]pyridine-Nglycinylhydrazones 63 which acted as good inhibitors of the tumour necrosis factor alpha (TNF − α) production. These compounds were synthesized in three steps employing the GBBR as the key reaction.…”

“…Imidazo [1,2-a]pyridine-N -glycinylhydrazones synthesized by Lacerda et al [82] were structural analogues of the orally active anti-inflammatory prototype p38 MAPK inhibitors: BIRB-796 87, LASSBio-1504 88 and SB-203580 89 [82]. For diversification purposes, the N -phenyl-pyrazole nucleus of LASSBio-1504 was replaced by the isosteric heterocycles imidazo [1,2-a]pyridine.…”

“…18). Furthermore, evaluation of the corresponding cytotoxicity and selectivity index revealed that LASSBio-1749 90 was safer than LASSBio-1504 88 and SB-203580 89 [82]. [78] were used as potential kinase inhibitors.…”

A new class of potential antidiabetic acetohydrazides: Synthesis, in vivo antidiabetic activity and molecular docking studies

“…N'-substituted benzylidene-2-(2,4-dimethyl-phenoxy) acetohydrazides are known to possess antibacterial and enzyme inhibition activities (Nadeem et al, 2014) whereas acetohydrazide derivatives of 2-aminopyridine are intended as inhibitors of tumor necrosis factor alpha (TNF-a) production (Lacerda et al, 2014).…”