Title:Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants
Volume: 24
Issue: 3
Author(s): Neela M. Bhatia, Manish S. Bhatia*, Sibaprasad K. Mohanty, Rishikesh S. Parulekar, Amruta V. Joshi and Snehal S. Ashtekar
Affiliation:
- Department of Pharmaceutical Chemistry, BharatiVidyapeeth College of Pharmacy, Kolhapur, India.
Keywords:
Tracheal smooth muscle relaxants, combinatorial synthesis, polyfunctional N-heteroarylamides, LTB4, Asthma, inhaled corticosteroids (ICS).
Abstract:
Introduction: Asthma complications and adverse effects associated with steroidal therapy
highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple
targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect
of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides.
Methods: Virtual screening and molecular docking studies of designed compounds were performed
using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor.
Cross-validation of virtual screening results and active site, confirmation was performedusingVlife
MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in
which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution
reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by
infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated
for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle.
Results: Results were calculated as a percent decrease in contraction response observed using histamine
and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity.
Based on the results of screening the structure-activity relationships (SAR) have been reported.
Conclusion: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal
smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual
screening results. A good correlation was observed between virtual screenings and biological activities
of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for
selected targets is appropriate.
