DFT study on the oxygen transfer mechanism in nitroethenediamine based H 2 -receptor antagonists using the bis-dithiolene complex as the model catalyst for N-oxide reductase enzyme Devendra K. Dhaked, Prasad V. Bharatam ⁎ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S., Nagar 160 062, Punjab, India abstract article info Article history: Received 4 April 2014 Received in revised form 17 September 2014 Accepted 18 September 2014 Available online 28 September 2014 Keywords: Nitroethenediamine Density Functional Theory N-oxide Tautomers Bis-dithiolene complex N-oxide reductase Nitroethenediamine is an important functional unit, which is present in H 2 -receptor antagonists. These drugs show low bioavailability due to the bacterial degradation caused by the N-oxide reductase type of enzymes present in the human colon. Quantum chemical studies have been carried out to elucidate the mechanism of metabolic degradation of nitroethenediamine in the active site of N-oxide reductase. Three different pathways have been explored for the N-oxide bond cleavage by the model system, Mo(IV) bis-dithiolene complex [Mo(OMe)(mdt) 2 ] - , (where mdt = 1,2-dimethyl-ethene-1,2-dithiolate) using B3LYP/6-311+G(d,p) and M06/6-311+G(d,p) Density Functional Theory methods. The oxygen atom transfer from the nitrogen atom of nitroethenediamine to the Mo(IV) complex, involves simultaneous weakening of the N-oxide bond and the formation of Mo–O bond through a least motion path. During this transfer, Mo center is converted from a square pyramidal geometry to a distorted octahedral geometry, to facilitate the process of oxygen atom transfer. The en- ergy barrier for the oxygen atom transfer from the imine tautomer has been estimated to be 25.9 kcal/mol how- ever, the overall reaction has been found to be endothermic. On the other hand, oxygen transfer reaction from the nitronic acid tautomer requires 30.5 kcal/mol energy leading to a highly exothermic metabolite (M-1) directly hence, this path can be considered thermodynamically favorable for this metabolite. The alternative path involv- ing the oxygen atom transfer from the enamine tautomer requires comparatively a higher energy barrier (32.6 kcal/mol) and leads to a slightly endothermic metabolite. This study established the structural and energetic details associated with the Mo(IV) bis-dithiolene complex that catalyzes the degradation of nitroethenediamine based drug molecules. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Ranitidine, a histamine H 2 -receptor antagonist (a blockbuster drug), inhibits acid production in stomach. It is used for the treatment of acid reflux, heartburn, ulcer and treatment of Zollinger–Ellison syndrome [1]. Nizatidine is available as an alternative H 2 -receptor antagonist (Fig. 1). Niperotidine is also H 2 -receptor antagonist, withdrawn from its active use due to hepatotoxicity [2,3]. The active functional moiety in these drugs is a nitroethenediamine unit (NED). Several reports indicated the existence of nitro ⇌ aci-nitro tautomerism [4,5] in NED based drug molecules [6] and this phenomenon is responsible for the observed different polymorphic states of these molecules [7,8]. Raniti- dine and nizatidine can exist in four tautomeric forms: enamine, imine, nitronic acid and nitrolic. Of these, the nitrolic form is a very high-energy tautomer [6]. Bioavailability is an important factor, which governs the mode of ac- tion, dose, potency, efficacy, toxicity, etc. of the drug molecules. The sys- temic bioavailability of any drug molecule is mainly affected by the metabolism and its rate of absorption. Bioavailability of ranitidine is poor due to the absorption in the initial part of the small intestine [9]. In addition, ranitidine is metabolized in human liver to ranitidine-N- oxide, ranitidine-S-oxide and desmethylranitidine metabolites via oxi- dation mechanism [10,11]. Williams et al. [12] reported that ranitidine was significantly less absorbed from the human colon as compared to the upper regions of the gut. Basit et al. [13,14] carried out experimental studies on several H 2 -receptor antagonists and observed that only NED based drugs (ranitidine and nizatidine) were found to be susceptible to colonic bacterial degradation. They suggested that both ranitidine and nizatidine are metabolized and degraded in the presence of a bacterial N-oxide reductase enzyme of colonic microflora, and this metabolism may be responsible for poor absorption, which eventually leads to poor bioavailability. It was proposed that the enamine tautomer of ranitidine tautomerizes to the nitronic acid tautomer, which is actively involved in colonic bacterial degradation (Fig. 2, Pathway-1). In this pathway, N-oxide bond cleavage originates from the nitronic acid Journal of Inorganic Biochemistry 142 (2015) 84–91 * Corresponding author. E-mail address: pvbharatam@niper.ac.in (P.V. Bharatam). http://dx.doi.org/10.1016/j.jinorgbio.2014.09.011 0162-0134/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio