Synthesis, in vitro biological evaluation and in silico studies of certain arylnicotinic acids conjugated with aryl (thio)semicarbazides as a novel class of anti-leishmanial agents

Eur J Med Chem. 2019 Oct 1:179:335-346. doi: 10.1016/j.ejmech.2019.06.051.

Wagdy M Eldehna ¹, Hadia Almahli ², Tamer M Ibrahim ³, Mohamed Fares ⁴, Tarfah Al-Warhi ⁵, Frank M Boeckler ⁶, Adnan A Bekhit ⁷, Hatem A Abdel-Aziz ⁸

Affiliations

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: wagdy2000@gmail.com.
2 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt.
3 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, 72076, Tuebingen, Germany. Electronic address: tamer.ibrahim2@gmail.com.
4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt; School of Chemistry, University of Wollongong, Wollongong, 2522, New South Wales, Australia.
5 Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
6 Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.
7 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, Kingdom of Bahrain.
8 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.

PMID: 31260888 DOI: 10.1016/j.ejmech.2019.06.051

Abstract

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.

Keywords

Anti-amastogite activity; Anti-folate mechanism; Anti-promastigote activity; Arylnicotinic acid - (thio)semicarbazide conjugates; Molecular modeling.

Name
Email *

	Sorry, but the email address you supplied was invalid.