ORIGINAL RESEARCH Pharmacophore modeling of some novel indole b-diketo acid and coumarin-based derivatives as HIV integrase inhibitors Shailesh V. Jain • Lalit V. Sonawane • Ravindra R. Patil • Sanjaykumar B. Bari Received: 12 March 2010 / Accepted: 18 November 2010 Ó Springer Science+Business Media, LLC 2010 Abstract To design new chemotypes with enhanced potencies against the HIV integrase enzyme, 3D pharma- cophore models were generated and QSAR study was carried out on 44 novel indole b-diketo acid derivatives and coumarin-based Inhibitors. A five-point pharmacophore with two hydrogen bond acceptors (A) and three aromatic rings (R) as pharmacophore features was developed by PHASE module of Schrodinger suite. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R 2 = 0.81 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of Q 2 = 0.69 for a randomly chosen test set of eight com- pounds. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may helps in the design and development of novel integr- ase inhibitors. Keywords Indole b-diketo acid derivatives Á Coumarin-based inhibitors Á Pharmacophore modeling Á 3D-QSAR Introduction Human immunodeficiency virus (HIV), a retrovirus, is the primary cause of acquired immunodeficiency syndrome (AIDS), and one of the main medical and social problems nowadays. HIV uses three key enzymes to propagate its life cycle; reverse transcriptase (RT), integrase (IN), and pro- tease (PR) (Michael et al., 2009; Bushman and Siegel, 2000; Verschueren et al., 2005). Inhibitors of HIV-1 integrase have emerged as a promising new class of ther- apeutics in the treatment of AIDS (Vandekerckhove et al., 2008). Although IN has long been regarded as a potentially attractive target for anti-HIV drug development, discovery of clinically relevant inhibitors has been challenging (Burke et al., 2008). Integrase functions in a two-step manner by initially removing a dinucleotide unit from the 3 0 -ends of the viral DNA (termed ‘‘3 0 -processing’’), with the 3 0 -processed strands then being transferred from the cytoplasm to the nucleus where they are introduced into the host DNA (termed ‘‘strand transfer’’ or ‘‘integration’’) (Pommier et al., 2006). Radiolabeled oligonucleotide- based assays (Katz et al., 1990; Craigie et al., 1991) which allows in vitro determination of IC 50 values for inhibition of both 3 0 -processing and strand transfer, have been utilized by several groups to examine the inhibitory efficacy of large numbers of agents (Burke et al., 1999). Different classes of HIV-1 IN inhibitors have been reported, e.g., an aryl 1,3-diketo containing compounds (i.e., 5CITEP (1B) and L-708,906), hydrazide derivatives, styrylquinoline derivatives, L-chicoric acid analogs, thiazolothiazepine derivatives, and cinnamoyl compound [such as curcumin derivatives (1) and caffeic acid phenethyl ester (CAPE) (2)] (Fig. 1; Vajragupta and Boonchoong, 2002). QSAR analyses of HIV-1 reverse transcriptase inhibitors (Pungpo and Hannongbua, 2000) HIV-1 protease inhibitors S. V. Jain (&) Á L. V. Sonawane Drug Design and Development, R. C. Patel Institute of Pharmaceutical Education and Research, Dhule District, Shirpur, Maharashtra 425405, India e-mail: shal.jain2007@gmail.com R. R. Patil Á S. B. Bari Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Dhule District, Shirpur, Maharashtra 425405, India Med Chem Res DOI 10.1007/s00044-010-9520-1 MEDICINAL CHEMISTR Y RESEARCH