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. 2023;24(3):257-266.
doi: 10.2174/1389203724666230220140700.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants

Neela M Bhatia  1 , Manish S Bhatia  2 , Sibaprasad K Mohanty  2 , Rishikesh S Parulekar  2 , Amruta V Joshi  2 , Snehal S Ashtekar  2
Affiliations

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants

Neela M Bhatia et al. Curr Protein Pept Sci. 2023.

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.

Keywords: Asthma; LTB4; Tracheal smooth muscle relaxants; combinatorial synthesis; inhaled corticosteroids (ICS); polyfunctional N-heteroarylamides.

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