International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol.4, No.3, pp 1110-1121, July-Sept 2012 QSAR Studies of N-(2-Aminophenyl)-Benzamide derivatives as Histone deacetylase2 I nhibitors Naresh Kandakatla 1,2,* , Geetha Ramakrishnan 2 , S. Vadivelan 1 and SarmaJagarlapudi 1 1 GVK Biosciences Pvt. Ltd., 443, Guna complex, 9th Floor, Annexe I Building, Anna salai, Teynampet, Chennai – 600 018, India 2 Department of Chemistry, Sathyabama university, Jeppiaar Nagar, Chennai-600119, India *Corres.author: nareshkandakatla7@gmail.com, Tel., +919003069189, +91 44 66293000; fax: +91 44 66293299. Abstract: Histone deacetylase 2 is a promising target for drug intervention and its inhibitors are useful in treating cancer. QSAR (2D and 3D) studies were performed on a series of N-(2-Aminophenyl)-Benzamide derivatives using Cerius2 software (accelrys). QSAR study performed on 25 analogues of which 21 were used in the training set and the rest 4 considered for the test set. 2D- QSAR study performed using Partial least squares (PLS), Genetic function approximation (GFA), Genetic partial least squares (G/PLS). Among these three methods GFA method came out with good correlation coefficient r 2 0.794, cross-validated coefficient r 2 CV 0.634 and r 2 pred of 0.6343. 3D-QSAR studies using Molecular field analysis (MFA), Regression analysis were carried out using GFA method. A highly predictive and statistically significant model was generated. The analyzed MFA model demonstrated a good fit, having r 2 value of 0.927, cross-validated coefficient r 2 CV value of 0.815 and r 2 pred of 0.845.The QSAR models were found to accurately predict the Histone deacetylase2 inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the N- (2-Aminophenyl)-Benzamide derivatives in the data set. Key words: Histone deacetylase 2; Genetic Function Approximation; Molecular field analysis; N-(2- Aminophenyl)-Benzamide derivatives. 1. Introduction: Histone deacetylase (HDACs) represent a family of enzymes that compete with histone acetyltransferases (HATs) to modulate chromatin structure and transcriptional activity via change in acetylation status of nucleosomal histones. HDACs are deacetylating the -amino groups of lysine located near the amino termini of core histone proteins [1-2] . Mammalian HDACs have been classified into three classes. Class I (HDACs 1, 2, 3 and 8) are homologs of yeast RPD3 and localize to the nucleus; Class II (HDACs 4, 5, 6, 7, 9 & 10) are homologs of yeast Hda1 and are found in both the nucleus and cytoplasm; Class III (Sirt1 - Sirt7). Class I and II HDACs operate by zinc-dependent mechanisms and Class III by NAD [3] . HDAC2 highly homologous to HDAC1 is a class I HDAC