Authors: Eldehna W.M., Almahli H., Ibrahim T.M., Fares M., Al-Warhi T., Boeckler F.M., Bekhit A.A., Abdel-Aziz H.A.
Author Affiliations: Eldehna, W.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; Almahli, H., Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt; Ibrahim, T.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt, Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen, 72076, Germany; Fares, M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt, School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia; Al-Warhi, T., Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; Boeckler, F.M., Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen, 72076, Germany; Bekhit, A.A., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt, Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain; Abdel-Aziz, H.A., Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt
Publication Date: 2019
Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazide derivatives. Based on a structure-guided approach, they were designed to possess anti-leishmanial activity through anti-folate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro anti-promastigote and anti-amastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine. The most active compounds 8i and 8j exhibited their anti-amastigote activity with IC50 values of 4.2 and 3.3 μM, respectively, compared to reference miltefosine (IC50 value of 7.3). Their anti-folate mechanism was confirmed via the ability of folic and folinic acids to reverse the anti-leishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Interestingly, the in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells. Furthermore, the docking experiments on Lm-PTR1 as a putative target rationalized the in vitro anti-leishmanial activity. The in silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. Generally, this work introduces a fruitful matrix for new anti-leishmanial chemotype which would extend the chemical space for the anti-leishmanial activity. © 2019 Elsevier Masson SAS
Eshan2020-11-28T18:18:46+00:00
