TY - JOUR
T1 - Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt
T2 - Potential lead compounds for treatment of secretory diarrhea
AU - Dawurung, Christiana J.
AU - Noitem, Rattikarn
AU - Rattanajak, Roonglawan
AU - Bunyong, Ratchanu
AU - Richardson, Christopher
AU - Willis, Anthony C.
AU - Kamchonwongpaisan, Sumalee
AU - Yimnual, Chantapol
AU - Muanprasat, Chatchai
AU - Pyne, Stephen G.
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/11
Y1 - 2020/11
N2 - A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− channel and calcium-activated Cl− channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl− secretion across T84 cell monolayers with IC50 values of ~0.81 μM, ~2.42 μM, ~2.87 μM, and ~4.66 μM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl− channel (TMEM16A) with an IC50 value of ~4.38 μM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 μM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 μg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 μM and 57.30 + 6.77 μM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.
AB - A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− channel and calcium-activated Cl− channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl− secretion across T84 cell monolayers with IC50 values of ~0.81 μM, ~2.42 μM, ~2.87 μM, and ~4.66 μM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl− channel (TMEM16A) with an IC50 value of ~4.38 μM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 μM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 μg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 μM and 57.30 + 6.77 μM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.
KW - Antidiarrheal
KW - CFTR
KW - Cytotoxicity
KW - Fabacae
KW - Neorautanenia mitis
KW - Nigerian traditional medicine
KW - Phytochemical
KW - TMEM16A
UR - http://www.scopus.com/inward/record.url?scp=85089340983&partnerID=8YFLogxK
U2 - 10.1016/j.phytochem.2020.112464
DO - 10.1016/j.phytochem.2020.112464
M3 - Article
SN - 0031-9422
VL - 179
JO - Phytochemistry
JF - Phytochemistry
M1 - 112464
ER -