Research paper Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling Mebarka Alloui a,b , Salah Belaidi a,⇑ , Hasna Othmani b,c , Nejm-Eddine Jaidane c , Majdi Hochlaf b,⇑ a University of Biskra, Faculty of Sciences, Department of Chemistry, Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, 07000 Biskra, Algeria b Université Paris-Est, Laboratoire Modélisation et Simulation Multi Echelle, MSME UMR 8208 CNRS, 5 bd Descartes, 77454 Marne-la-Vallée, France c Laboratory of Atomic Molecular Spectroscopy and Applications, Department of Physics, Faculty of Sciences, University Tunis El Manar, Campus Universities, 1060 Tunis, Tunisia article info Article history: Received 29 November 2017 In final form 15 February 2018 Available online 16 February 2018 abstract We performed benchmark studies on the molecular geometry, electron properties and vibrational anal- ysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combina- tion of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model. Ó 2018 Elsevier B.V. All rights reserved. 1. Introduction The field of computational medicinal chemistry comprises com- putational approaches for the design, the development and the synthesis of pharmacologically active compounds [1]. It can help make cost-effective decisions before expensive synthesis starts [2]. Among the approaches that are widely used for those purposes, quantitative structure-activity relationships (QSAR) modeling attempts to find consistent relationships between the variations in the values of molecular properties and the biological activity of compounds [3]. QSAR models are essential to optimize the struc- ture that gives the desired biological activities [4]. Commonly, we use semi-empirical approaches for the elaboration of models, which are based on measured values of the property to be mod- eled. Up-to-date methods used in QSAR modeling include statisti- cal regression techniques (e.g., multiple linear regressions (MLR) [5]). Imidazole is a five-membered ring heterocyclic compound con- taining two nitrogen atoms [6] (Scheme 1). This cycle can be found in several natural compounds, such as alkaloids. It is also present in important biological building blocks (e.g., histidine) and drugs. For instance, imidazole derivatives exhibit various pharmacological activities as antiviral, anti-inflammatory, analgesic, antidepressant, anti-fungal, anti-bacterial and anti-cancer agents [7]. In biological media, imidazole and imidazolate act as ligands to Zn 2+ cation and their complexes constitute the main part of the active sites of a large class of metalloenzymes, which are involved in funda- mental physiological processes [8] such as respiration, photosyn- thesis, or acid–base balance of all living organisms [9]. On the other hand the complexes between Zn 2+ and imidazole are sub- units of zeolitic imidazolate frameworks (ZIFs), which are con- structed from tetrahedral units formed by one bivalent metal ion (M 2+ = Zn 2+ /Co 2+ ) linked to four imidazolate anions [10,8]. ZIFs show high stability, large structural diversity and high porosity leading to important industrial applications, including capture, storage and selective sequestration of gases (e.g., CO 2 ) [9,10]. Imi- dazole derivatives are also used as corrosion inhibitors [11]. Because of their importance, several imidazole derivatives were widely studied in order to find a relation between their structure and their activity using QSAR approaches as can be seen in several recent reviews and articles [12,13]. Let’s cite, for instance, the QSAR analysis by Khalafi-Nezhad et al. to investigate the quantita- tive effect of structural properties of some imidazole and benzim- idazole chloro-aryloxy alkyl derivatives on their antibacterial activity [13]. In this contribution, we study a series of 31 imidazole deriva- tives reported by Olson et al. [14] in 1994. These compounds are known to act as angiotensin II AT1 G protein-coupled receptor blockers [14]. They are specified in Scheme 1 and Table 1. There is high-structural diversity of the biological activity in the selected https://doi.org/10.1016/j.cplett.2018.02.048 0009-2614/Ó 2018 Elsevier B.V. All rights reserved. ⇑ Corresponding authors. E-mail addresses: prof.belaidi@gmail.com (S. Belaidi), hochlaf@univ-mlv.fr (M. Hochlaf). Chemical Physics Letters 696 (2018) 70–78 Contents lists available at ScienceDirect Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett