Development of a Novel Class of Pyridazinone Derivatives as Selective

Abstract

Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 mu M, followed by TR2 (IC50 = 0.27 mu M). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with K-i values of 0.230 +/- 0.004 and 0.149 +/- 0.016 mu M, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.

C1 [Alagoz, Mehmet Abdullah; Zenni, Yaren Nur; Ozdemir, Zeynep] Inonu Univ, Fac Pharm, Dept Pharmaceut Chem, TR-44280 Malatya, Turkey.

[Oh, Jong Min; Kim, Hoon] Sunchon Natl Univ, Dept Pharm, Sunchon 57922, South Korea.

[Oh, Jong Min; Kim, Hoon] Sunchon Natl Univ, Res Inst Life Pharmaceut Sci, Sunchon 57922, South Korea.

[Abdelgawad, Mohamed A.] Jouf Univ, Coll Pharm, Dept Pharmaceut Chem, Sakaka 72341, Al Jouf, Saudi Arabia.

[Naguib, Ibrahim A.] Taif Univ, Coll Pharm, Dept Pharmaceut Chem, POB 11099, Taif 21944, Saudi Arabia.

[Ghoneim, Mohammed M.] AlMaarefa Univ, Fac Pharm, Dept Pharm Practice, Ad Diriyah 13713, Saudi Arabia.

[Gambacorta, Nicola; Nicolotti, Orazio] Univ Bari Aldo Moro, Dipartimento Farm Sci Farmaco, Via E Orabona 4, I-70125 Bari, Italy.

[Mathew, Bijo] Amrita Vishwa Vidyapeetham, Dept Pharmaceut Chem, Amrita Sch Pharm, AIMS Hlth Sci Campus, Kochi 682041, Kerala, India.