Full Paper Some Hydrazones of 2-Aroylamino-3-methylbutanohydrazide: Synthesis, Molecular Modeling Studies, and Identification as Stereoselective Inhibitors of HIV-1 Esra Tatar 1 ,I ˙ lkay Ku ¨c ¸u ¨ kgu ¨ zel 1 , Dirk Daelemans 2 , Tanaji T. Talele 3 , Neerja Kaushik-Basu 4 , Erik De Clercq 2 , and Christophe Pannecouque 2 1 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Marmara University, Haydarpas ¸a, I ˙ stanbul, Turkey 2 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium 3 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA 4 Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ, USA In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 S , 11 S , and 12 S showed anti-HIV-1 activity with a 50% inhibitory concentration (IC 50 ) ¼ 123.8 mM (selectivity index, SI > 3), IC 50 ¼ 12.1 mM (SI > 29), IC 50 ¼ 17.4 mM (SI > 19), respectively. Enantiomers 8 R , 11 R , and 12 R were inactive against the HIV-1 strain III B . Hydrazones 8 S , 11 S , and 12 S which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT. Keywords: Acylhydrazones / HIV-1 / Molecular modeling / Non-nucleoside reverse transcriptase inhibitors / Stereoselective activity Received: August 22, 2012; Revised: October 10, 2012; Accepted: October 17, 2012 DOI 10.1002/ardp.201200311 : Additional supporting information may be found in the online version of this article at the publisher’s web-site. Introduction Infection with human immunodeficiency virus (HIV), the etio- logical agent of acquired immune deficiency syndrome (AIDS), is a significant global concern. Drug development efforts aimed at suppressing the viability, replication, and virulence of HIV have resulted in a number of active anti-HIV compounds, 26 of which have been FDA-approved to date. These clinically avail- able compounds can be broadly classified into six groups according to their targets and mode of action in the HIV replicative cycle. These include the nucleoside reverse tran- scriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibi- tors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors [fusion inhibitors (FIs) and co-receptor inhibitors (CRIs)], and integrase inhibitors (INIs) [1]. Despite these advances, there exists a pressing need to develop new treatment strategies for AIDS due to the emergence of drug-resistant HIV variants. To infect its hosts, HIV uses three essential enzymes: HIV reverse transcriptase (HIV-RT), integrase (IN), and protease (PR) [2]. Among these, HIV-1 RT has been a major target for antiretroviral drug development and more than half of the currently approved drugs for the treatment of HIV-1 infection are RT inhibitors [3]. Conversion of the single stranded RNA genome into a double stranded DNA is the primordial func- tion of HIV-1 RT. HIV-1 RT consists of a p66 and a p51 subunit and thus acts as a heterodimer. Despite the structural role of the p51 subunit as elucidated by means of conformational modifications, the NNRTI-binding pocket (NNRTI-BP), poly- merase, and RNase H domains are located in the p66 subunit [4]. The NNRTI-BP with hydrophobic and hydrophilic residues Correspondence: I ˙ lkay Ku ¨c ¸u ¨kgu ¨zel, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Marmara University, Haydarpas ¸a, 34668 I ˙ stanbul, Turkey. E-mail: ikucukguzel@marmara.edu.tr Fax: þ90 216 345 29 52 140 Arch. Pharm. Chem. Life Sci. 2013, 346, 140–153 ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim