Contents lists available at ScienceDirect Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb Biochemistry Synthesis and characterization of new 1-hydroxy-2-pyridinethione derivatives: Their lead complexes and efficacy in the treatment of acute lead poisoning in rats Manal H. Al Khabbas a , Samah A. Ata b , Kamal I. Abu-Dari c, ⁎ , Maha F. Tutunji c,1 , Mohammad S. Mubarak c, ⁎ a Chemistry Department, Faculty of Science, University of Hail, PO Box 2440, Saudi Arabia b Pharmacy Department, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, 130, Amman 11733, Jordan c Department of Chemistry, Faculty of Science, The University of Jordan, Amman 11942, Jordan ARTICLE INFO Keywords: Pyridinethiones Chelation therapy Acute lead poisoning Subchronic lead poisoning Rats ABSTRACT A number of new mono- and dihydroxypyridinethione ligands have been synthesized via reaction of dimethy- lamine and amino acid esters with the active amide obtained from the reaction of 1-hydroxy-2-pyridinethione-4- carboxylic acid (1) and 1,1′-carbonyldiimidazole in DMF. Moreover, the lead complexes of these new ligands were also prepared. Structures of the newly synthesized compounds have been confirmed by different spec- troscopic methods such as IR, 1 H NMR, and 13 C NMR, and by elemental analysis. The effect of these synthesized ligands on the excretion of lead, iron, and zinc, and their distribution in kidneys, liver, and bones in acutely intoxicated rats was investigated and results, for lead, were compared with those of the known drug meso-2,3- dimercaptosuccinic acid (DMSA). Results obtained revealed that compound 5 exhibits remarkable ability in total fecal and urinary excretion of lead and was superior to DMSA. In addition, results show that the concentration of lead in soft tissues and bones was lower in rats treated with HTPL than those treated with DMSA. Furthermore, the concentration of lead in liver tissues obtained from sub-chronic lead-intoxicated rats treated with HTPL was lower than those treated with DMSA and calcium disodium ethylenediaminetetraacetic acid (CaNa 2 EDTA). 1. Introduction Lead (Pb) is one of the most toxic non-essential metals, an en- vironmental and occupational pollutant that endangers human health. Exposure to lead can occur via different means such as contaminated air, water, dust, food, or consumer products. Exposure to lead whether at work or through other means is a common cause of lead poisoning in adults with certain occupations at particular risk [1,2]. Therefore, lead in the body can result in lead poisoning, especially the brain which is the most sensitive organ to this effect [3]. In the USA, The Centers for Disease Control (CDC) has set the upper limit for blood lead for adults at 10 mg/dL (10 μg/100 g) and for children at 5 μg/dL [4]. In addition, children younger than 6 years are especially vulnerable to lead poi- soning, which can severely affect mental and physical development, and at very high levels, can be fatal [3]. Furthermore, lead, which has no known essential biological function, is absorbed, as an element or in the form of compounds, by humans through skin, gastrointestinal tract, and lungs. Owing to its slow elimination, it accumulates in the liver, bones, and many other parts of the body [5]. Lead poisoning has been diagnosed in people irrespective of age, race, or geographic region [6,7], and affects the functions of almost all organs in the body in- cluding blood, kidneys, liver, testes, brain, and central nervous system [8,9]. Additionally, it has the affinity to bind to many functional groups including sulfhydryl, amine, phosphate, and carboxylic groups, and thus interferes with the functions of many enzymes as well as in the heme synthesis [10]. Chelation therapy is the recommended treatment of lead poisoning [10–13]. This is accomplished through the use of chelating agents that bind toxic lead and selectively remove it from circulation, and promote the removal of lead ions that are reversibly bound to enzymes and other tissue components [14]. Several chelating agents have been used in the chelation therapy of lead poisoning [15] including EDTA or CaEDTA [16], 2-mercaptosuccinic acid [17], 2,2-dimercaptosuccinic acid (DMSA) [18], a combination of EDTA and DMSA [19], N-(2-hydro- xyethyl)ethylenediaminetriacetic acid (HEDTA) [20], and many others. However, some of these compounds are nonspecific [19] or relatively http://dx.doi.org/10.1016/j.jtemb.2017.08.004 Received 23 June 2017; Received in revised form 27 July 2017; Accepted 2 August 2017 ⁎ Corresponding authors. 1 Deceased. E-mail addresses: abudarik@ju.edu.jo (K.I. Abu-Dari), mmubarak@ju.edu.jo (M.S. Mubarak). Journal of Trace Elements in Medicine and Biology 44 (2017) 209–217 0946-672X/ © 2017 Elsevier GmbH. All rights reserved. MARK