Design, Synthesis, and Biological Evaluations of Several Fasudil Analogues

Abstract

In our previous work, (S)‐6H‐1‐(5‐isoquinolinesulfonyl)‐2‐hydroxymethyl‐1‐pyrrolidine and (S)‐6H‐1‐(5‐isoquinolinesulfonyl)‐2‐chloromethyl‐1‐pyrrolidine displayed potent inhibitory activity. Therefore, with these two substances as lead compounds, we designed and synthesized their enantiomers to reveal the inhibitory effects of chirality on Rho kinase. It is found that their enantiomers exhibited much better Rho kinase inhibitory activity and strongly promoted synapse formation. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. With added antigens, the changes from C57BL/6 mice's limbs and tail was observed and scored by clinical evaluation. The synthetic compounds may simultaneously reduce symptoms of experimental autoimmune encephalomyelitis and inhibit inflammatory infiltration of the central nervous system. Thus, these compounds may be potential candidates for inhibition of Rho kinase and should be considered for further experimental study in relation to multiple sclerosis.

Catalyst‐free Chloroamination Cyclization Cascade with Sodium Hypochlorite: from N‐(Pentenyl)sulfonylamides to 2‐(1‐Chloromethyl)pyrrolidines

“…[4] When a chlorine atom is introduced in the vicinal position to the nitrogen atom, 2-chloromethylpyrrolidines are produced. The relevance of this motif is illustrated in Figure 1, where drugs analogues, [5] potential drug candidates, [6] and natural products [7] containing this moiety are represented. Organochlorine compounds are, also, important building blocks for organic chemistry serving as precursors for amines, alcohols, thio/ethers, and organometallic reagents.…”