Affiliation:
1. Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya (A Central University), Sagar 470003, Madhya
Pradesh, India
2. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
Abstract
Abstract:
Cytochrome P450 3A4, the most abundant form of isoenzyme, in combination
with several other isoforms, metabolizes lignocaine into mono-ethylglycine xylidide
(MEGX) and glycylxylidide (GX), through N-dealkylation, ring hydroxylation, amide
cleavage, and conjugation process which contribute the toxic effects. Inspiring by the rationality,
functional approaches, and predictable facts lay by the emerging research groups,
we were unquestionably fascinated by the rational development of novel lignocaine and
etidocaine compounds, which are highly metabolically stable by applying non-classical
bioisosteric principles. Distinctively, we have investigated the efficacy of 1,4-
disubstituted-1,2,3-triazoles as metabolically stable trans-amide bond mimics. The 1,2,3-
triazoles have been described in the literature as amide bond bioisosteres, which are analogous
in stipulations of size, planarity, hydrogen bonding properties, and dipole moment. The systematic replacement
of the single amide bonds by the 1,2,3-triazole heterocycle in the backbone of the peptide, often
termed a “triazole scan,” provided several stabilized analogs with marked improved in-vivo local anesthetic
properties. The analogs were synthesized using azide-alkyne cycloaddition. The 2a-b was coupled with aromatic
and aliphatic alkynes using click chemistry in the presence of copper sulfate pentahydrate and L-sodium
ascorbate in a Fritsch ball mill under solvent-free conditions at 300 rpm, furnishing the conjugates 4a-n in 80-
85% yields. The study perceptively opened new avenues of systematic replacement of the single amide bonds
by the 1,2,3-triazole heterocycle in the backbone of the peptide, thereby providing several stabilized analogs
with marked improved in-vivo local anesthetic properties. The best active candidates 4a, 4b and 4g produced
analogous local anesthetic activity with that of the lignocaine.
Publisher
Bentham Science Publishers Ltd.