Synthesis and evaluation of quinazoline amino acid derivatives as mono amine oxidase (MAO) inhibitors Sherine Nabil Khattab a,⇑ , Nesreen Saied Haiba b , Ahmed Mosaad Asal b , Adnan A. Bekhit c,⇑ , Adel Amer a,d , Hamdy M. Abdel-Rahman e , Ayman El-Faham a,f,⇑ a Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Ibrahimia, Alexandria 21321, Egypt b Department of Physics and Chemistry, Faculty of Education, Alexandria University, Egypt c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt d Department of Applied Chemistry, Faculty of Applied Science, Taibah University, Saudi Arabia e Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt f Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia article info Article history: Received 6 February 2015 Revised 30 March 2015 Accepted 9 April 2015 Available online 16 April 2015 Keywords: Isatoic anhydride Amino acids Quinazolinones Monoamine oxidase abstract A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC 50 = 3.6 Â 10 À9 , 2.8 Â 10 À9 , 2.1 Â 10 À9 M, respectively) comparable to that of the standard clorgyline (IC 50 = 2.9 Â 10 À9 M). 2-(2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohy- drazide 15 showed selective MAO-A inhibition activity (SI = 39524) superior to that of the standard clorgyline (SI = 33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction Monoamine oxidase A and B (MAO-A and -B) are flavin adenine dinucleotide (FAD) containing enzymes, which are localized in the outer mitochondrial membranes of neuronal, glial, and other cells 1 particularly abundant in the liver and brain. 2 These FAD dependent enzymes are responsible for regulation and metabolism of major monoamine neurotransmitters such as serotonin (5-OH trypta- mine), nor-adrenaline and dopamine. It is also involved in the biodegradation of exogenic amines such as benzylamine, tyramine, MPTT, MPP+ and a Parkinsonian producing neurotoxin. 1 It cat- alyzes the oxidative deamination of a range of endogenous and exogenous monoamines. 3 The two mammalian isoforms are encoded by two different genes 4 and distinguished by different substrate specificities and sensitivities to the selective inhibitors. 5 Thus, MAO-A is selectively inhibited by clorgyline and metabolizes serotonin preferentially, whereas MAO-B is inhibited by l-deprenyl and prefers benzylamine and phenylethylamine as substrates. Selective MAO-A inhibitors are used clinically as antidepressants and anxiolytics, while MAO-B inhibitors are used for reduction of the progression of Parkinson’s disease and of symptoms associated with Alzheimer’s disease. Earlier MAO inhibitors introduced into clinical practice for the treatment of depression were abandoned due to adverse side-effect, such ‘cheese effect’ characterized by hypertensive crises. 6 In spite of considerable progress in understanding of the inter- actions of the two enzyme forms with their preferred substrates and inhibitors, no general rules are yet available for the rational design of potent and selective inhibitors of MAO. This is partly due to the fact that the mechanism of interaction of several new drugs with MAOs has not been fully characterized. Therefore, the discovery of several selective MAO inhibitors has relied on serendipity. For this reason, research has been directed at the syn- thesis of new potential agents with clinical practice. Among these targeted compounds are heterocyclic hydrazines and hydrazides. Their prototype, N 0 -propan-2-ylpyridine-4-carbohydrazide, was the first modern antidepressant and was introduced into the http://dx.doi.org/10.1016/j.bmc.2015.04.021 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. E-mail addresses: sh.n.khattab@gmail.com (S.N. Khattab), nesreensaied@yahoo. com (N.S. Haiba), adnbekhit@hotmail.com (A.A. Bekhit), adel.amer@alex-sci.edu.eg (A. Amer), hamdym01@yahoo.com (H.M. Abdel-Rahman), aymanel_faham@ hotmail.com (A. El-Faham). Bioorganic & Medicinal Chemistry 23 (2015) 3574–3585 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc