Twelve pyridazinones (T1-T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 mu M, followed by T3 (IC50 = 0.039 mu M). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)(2) (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 mu M and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with K-i values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.
C1 [Cecen, Muhammed; Ozdemir, Zeynep] Inonu Univ, Dept Pharmaceut Chem, Fac Pharm, 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.
[Buyuktuncel, Saliha Ebru] Inonu Univ, Dept Analyt Chem, Fac Pharm, TR-44280 Malatya, Turkey.
[Uysal, Mehtap] Gazi Univ, Dept Pharmaceut Chem, Fac Pharm, TR-06100 Ankara, Turkey.
[Abdelgawad, Mohamed A.] Jouf Univ, Dept Pharmaceut Chem, Coll Pharm, Sakaka 72341, Al Jouf, Saudi Arabia.
[Abdelgawad, Mohamed A.] Beni Suef Univ, Fac Pharm, Dept Organ Pharmaceut Chem, Bani Suwayf 62514, Egypt.
[Musa, Arafa] Jouf Univ, Dept Pharmacognosy, Coll Pharm, Sakaka 72341, Al Jouf, Saudi Arabia.
[Musa, Arafa] Al Azhar Univ, Fac Pharm, Dept Pharmacognosy, Cairo 11371, Egypt.
[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, Amrita Sch Pharm, Dept Pharmaceut Chem, Amrita Hlth Sci Campus, Kochi 682041, Kerala, India.