Investigation on quantitatıve structure-activity relationshıps of benzoylamino benzoic acıd derivatives as β-ketoacyl-acyl carrıer protein synthase ııı (fabh) inhibitors

Marmara Pharmaceutical Journal 21/3: 631-643, 2017 DOI: 10.12991/marupj.323292 RESEARCH PAPER Investigation on quantitative structure-activity relationships of benzoylamino benzoic acid derivatives as β-ketoacyl-acyl carrier protein synthase III (FABH) inhibitors PP Subramani, SV Khare, SP Choudhari, SP Phalle, SS Kumbhar, VS Kavade, AA Pratavale, PB Choudhari ABSTRACT Fatty acid biosynthesis is an important process in the microorganism life cycle. β-Ketoacyl-acyl Carrier Protein Synthase III (FABH) catalyzes a critical step in fatty acid biosynthesis via type ii fatty acid biosynthesis. Series of 43 Benzoyl amino benzoic acid derivatives were subjected to 2D and 3D quantitative structure-activity relationships (QSAR) analysis via multiple linear regression and partial least square analysis respectively. Statistically significant four QSAR models were developed with good cross-validated correlation coefficient and external validation values. Developed QSAR model indicated the significance of the lipophilic parameters in an inhibitory potential of benzoyl amino benzoic acid derivatives. Keywords: QSAR, Benzoyl amino benzoic acid, FabHβKetoacyl-acyl Carrier Protein Synthase III, Partial least square (PLS), Multiple linear regression (MLR). Introduction: PP Subramani, SV Khare, SP Choudhari, SP Phalle, SS Kumbhar, VS Kavade, PB Choudhari Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra AA Pratavale Department of Chemistry, Shivaji University, Kolhapur Corresponding Author: P. B Choudhari e-mail: , Submitted / Gönderilme: 02.02.2017 Accepted / Kabul: 04.05.2017 Revised / Düzeltme: 22.03.2017 Tuberculosis (TB) is the most common infectious and lethal disease known to human. In recent decade mortality rate of tuberculosis is increased rapidly in developing countries [1]. In 1993, World Health Organization noted tuberculosis as a global emergency The problem of the tuberculosis is further aggravated by the emergence of the resistant form of tuberculosis like MDR, XDR, and TDR Association of tuberculosis with HIV-1 and 2 infections are major factors in the actual resurgence of tuberculosis. Development of the newer antitubercular agents targeting conservative pathways now becomes need of time in the current scenario [1-5]. One of the important strategies which are currently employed is to develop inhibitors of mycobacterial cell wall biosynthesis. The cell wall of the M. tuberculosis contributes significantly towards resistance to most commonly-used antibiotics and chemotherapeutic agents. The cell wall of the mycobacteria is made up of three major components macromolecules, peptidoglycan, arabinogalactan and mycolic acids which were covalent bound with each other [6-8]. Fatty acid biosynthesis is an important step in the cell wall generation in mycobacteria, it has been established that this fatty acid biosynthesis process 631 632 Subramani et al. 2D and 3D-QSAR models for benzoyl amino benzoic acid derivatives as FABH inhibitors may become the source of utilizable molecular targets due its non-homologous nature to mammalian system. Mycobacteria possess both a type I and type II fatty acid synthase in which type I fatty acid synthase is responsible for the formation of 1624 carbon length fatty acids, which are then elongated to form long chain high molecular mass mycolate. Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH) is a key enzyme plays important role in fatty acid bio synthesis. The enzyme FabH catalyzes the first step of fatty acid biosynthesis via a type II dissociated fatty acid synthase [9-10]. The important role of this enzyme in fatty acid biosynthesis and its conservative nature made it an attractive target for antitubercular drug design and development. Quantitative structure-activity relationships (QSAR) are the important methodologies in chemo metrics in which mathematical equations were generated for correlation of biological activity with structural properties. QSAR studies are of different types like 2D, 3D, 4D and GQSAR. In 2D QSAR analysis physiochemical properties were correlated with the biological potential to identify critical physicochemical parameters for optimization. 3D QSAR is more advanced than 2D where in 3D properties in terms of interactions energies are correlated with bioactivity [11-12]. In this research paper we are focused on development of 2D and 3D-QSAR models for benzoyl amino benzoic acid derivatives as Ketoacyl-acyl Carrier Protein Synthase III (FABH) inhibitors. Computational Methodology Dataset: A series of 43 3-phenoxybenzoylamino benzoic acid derivatives as β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors reported by Zhe Nieet. al and Ashek et. Al [14-16] was utilized to perform the QSAR study. Biological activity is expressed in terms of pMIC50 (-log MIC50) was utilized as a dependent variable and physicochemical parameters in terms of 2D and 3D descriptors are utilized as independent variables. Table 1 shows the structure of 43 selected derivatives along with their biological activity values. Selection of Training and Test Sets for Models Selected 3-phenoxybenzoylamino benzoic acid derivatives were drawn using 2D sketcher of Vlife engine 4.5. Derivatives were further optimized via converting into 3D structures keeping native bond angle and bond length intact. Energy minimization and geometry optimization of all 43 derivatives were carried out using Merck Molecular Force Field. Compounds were sketched using the 2D draw application Marmara Pharm J 21/3: 631-643, 2017 and converted to 3D structures. Energy minimization and geometry optimization was conducted using Merck molecular force field using batch energy minimization method. Dataset of all 43 molecules was randomly classified into training set (30 molecules) for the development of QSAR model and test set (13 molecules) for validation of developed models. Calculation of 2D and 3D-QSAR Descriptor: Molecular descriptors are acting as independent variables were calculated using QSAR module of V life MDS. Total 239 2D molecular descriptors were calculated which are consist of various physicochemical parameters. Molecular alignment is critical step to be followed by calculation of the 3D descriptors. Optimized molecules were aligned using template-based alignment. 3D field descriptor, were calculated using Tripos force field steric, electrostatic and hydrophobic field types, having cutoffs of 10.0 and 30.0 kcal/ mol using Gasteiger and Marsilli charges. More than 3000 3D descriptors were calculated but the invariable descriptors were eliminated prior to the QSAR model development. Model Validation: Generated QSAR models were validated using standard leave one out method. The formula for calculation of crossvalidated r2(q2) value was given in equation 1, where yi and ŷi are the actual and predicted activities of the ith molecule, respectively and ymean is the average activity of all m (...truncated)