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Chapter 3
Synthesis of trisubstituted pyrazoles/isoxazoles
N X
N
N
Antioxidant activity
N N
H H
R 1 =R 3 =H,
R 2 =OH,N(CH 3 ) 2
Antimicrobial activity
R 3 R 1 R 3 R 1
R 1 =R 3 =H,
R 2 R R 2 2 =N(CH 3 ) 2 ,OCH
X=O,NH
3
Figure-3
Annamaria Lilienkampf et al. 18 has developed isoxazole-based anti-TB
compounds by applying rational drug design approach (Figure-4). The biological
activity and the structure-activity relationships (SAR) for a designed series of 5-
phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were
investigated. Several compounds were found to exhibit nanomolar activity against the
replicating bacteria (R-TB) and low micromolar activity against the non replicating
bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in
general, no cytotoxicity was observed in Vero cells (IC 50 >128 μM). Notably, selected
compounds also retained their activity against isoniazid (INH), rifampin (RMP), and
streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and
phenoxy derivatives of5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a
highly potent, selective, and versatile series of anti-TB compounds and as such
present attractive lead compounds for further TB drug development.
R 1
R 5
R 2
R 3
O
O N
O
O
R 4
R 1 =H, CF 3 ,Cl,F,NO 2
R 2 =OCF 3 ,CH 3 ,NH 2 ,OCH 3 , CON(CH 2 CH 2 ) 2 O, H,Cl, F,
R 3 =H, CF 3 ,Cl,F,
R 4 =R 5 =H,F
Figure-4
Recently, biological evaluation of novel potent HDAC3 and HDAC8
isoxazole and pyrazole-based diazide probes (Figure-5) suitable for binding ensemble
profiling with photo affinity labeling (BEProFL) experiments in cells is described.
Both the isoxazole and pyrazole-based probes exhibit low nanomolar inhibitory
activity against HDAC3 and HDAC8, respectively. The pyrazole-based one of the
most active HDAC8 inhibitors reported in the literature with an IC 50 of 17 nM.
Department of Chemistry Saurashtra university, Rajkot-360005 84