Structural Design, Synthesis and Molecular Docking Studies of 6-[5-(Substituted Phenyl)-4,5-Dihydro-1H-Pyrazol-3-Yl]Pyrrolo[2,1-F][1,2,4]Triazin-4-Amine Derivatives as Anti-Inflammatory Agents

Abstract

Introduction:  Fused heterocycles are very capable of designing  new medications due to their propensity to provide selectivity.Pyrrolo[2,1-f] [1,2,4] triazine is a bicyclic heterocycle, containing N–N bond with bridgehead nitrogen possesses numerous activities against various therapeutic targets.Pyrazole and its derivatives are pharmacologically important active scaffold that possesses various pharmacological activities.

Objectives: To design, synthesize and evaluate anti-inflammatory activity of 6-[5-(Substituted phenyl)-4,5-dihydro-1H- pyrazol-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine and its derivatives.

Methods: Structural design of 6-[5-(Substituted phenyl)-4,5-dihydro-1H- pyrazol-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives were synthesized, and evaluated for their potential as anti-inflammatory agents. Pyrrolotriazine was first synthesized from pyrrole carbaldehyde and hydroxylamine via pyrrole-2-carbonitrile followed by acetylation with acetyl chloride to yield acetyl-pyrrolotriazine. Subsequent condensation with substituted benzaldehyde gives pyrrolotriazine-based chalcones, which were cyclized using hydrazine hydrate to obtain the targeted compounds.All the synthesized derivatives were characterized by using spectroscopic techniques and evaluated its in-vitro anti-inflammatory activity.

Results: The Swiss ADME results revealed that none of the designed compounds violated Lipinski's rule of five.All the designed compounds showed potential binding affinity with PDB ID 6JVH   as anti-inflammatory activity.  Designed compounds R13, R14 and R15 showed docked scores -10.3, -10.4, and -9.9 kcal/mol whereas the reference drug Ibuprofen has a binding affinity of -7.9 kcal/mol. In-vitro anti-inflammatory activity of synthesized compounds were evaluated using the HRBC (Human Red Blood Cell) membrane stabilization method against ibuprofen as the standard.The results revealed that several synthesized compounds, namely R1, R2, R13, R14 and R15 showed significant  in-vitro anti-inflammatory activity.

Conclusions:  Among all these derivatives R13 showed highest anti-inflammatory activity indicating as lead molecule for further development into effective therapeutic agent.