Benzamide-Based Thiolcarbamates: A New Class of HIV-1NCp7 Inhibitors Atul Goel, a Sharlyn J. Mazur, a Rasem J. Fattah, b Tracy L. Hartman, c Jim A. Turpin, c Mingjun Huang, d William G. Rice, d Ettore Appella a and John K. Inman b, * a Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA b LaboratoryofImmunology,NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,Bethesda,MD20892,USA c Infectious Disease Research Department, Southern Research Institute, 431 Aviation Way, Frederick, MD 21702, USA d Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT O6511, USA Received 26 October 2001; accepted 17 December 2001 Abstract—The HIV-1 nucleocapsid protein NCp7, which contains two highly conserved zinc fingers, is being used as a novel target for AIDS therapy due to its pivotal role in viral replication and its mutationally intolerant nature. Herein we report a new class of NCp7 inhibitors that possess good antiviral activity with low cellular toxicity. # 2002 Elsevier Science Ltd. All rights reserved. The nucleocapsid p7 protein (NCp7) zinc finger domains of human immunodeficiency virus type 1 (HIV-1) have been chosen and exploited as targets in the pursuit of alternative, novel anti-retroviral drugs. 1 NCp7, a basic 55 amino acid protein, results from spe- cific post-translational processing of Pr55 gag and Pr160 gag-pol precursor polyproteins 2 and plays a pivotal role in both early (reverse transcription 3 and integra- tion 4 ) and late (protease processing 5 and packaging 6 of viral genomic RNA) stages of the viral replication cycle. The Cys-(Xaa) 2 -Cys-(Xaa) 4 -His-(Xaa) 4 -Cys (CCHC) motifs 7 are present in both zinc fingers of NCp7 and are highly conserved and mutationally intolerant. 8 Muta- tional studies on virus infectivity indicated that mod- ification in either zinc chelating, non-chelating and adjacent sequences of the zinc finger domains results in virions with defective RNA encapsidation and/or NCp7 function that renders them noninfectious. 6,9 A variety of electrophilic agents have been identified that cause HIV-1 inhibition by chemical modification of Cys-sulfurs of the NCp7 zinc finger motifs. Studies on NCp7 inhibitors, such as 3-nitrosobenzamide (NOBA), 10 2,2 0 -dithiobisbenzamides (DIBA) 1a,11 and their benz- isothiazolone derivatives (BITA), 12 cyclic 2,2 0 -dithio- bisbenzamides (SRR-SB3), 13 1,2-dithiane-4,5-diol-1,1- dioxide (dithiane), 14 and azodicarbonamide (ADA) 15 showed that these compounds exhibited significant antiviral activity against laboratory and clinical isolates of HIV in several infected cell lines. Recently, we iden- tified a novel chemotype, pyridinioalkanoyl thiolesters (PATEs), 16 that inhibits viral replication in both acutely and latently HIV-1 infected cells. PATEs possessed NCp7 zinc finger reactivity and virucidal activity. However, efforts to generate compounds with sig- nificantly improved antiviral potencies were not suc- cessful. The present study was focused on identifying a new class of NCp7 inhibitors, thiolcarbamates (TICAs), that possess improved anti-retroviral potency. 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00007-0 Bioorganic & Medicinal Chemistry Letters 12 (2002) 767–770 Scheme 1. Reagents and conditions: (i) N-Hydroxysuccinimide/DIC/ THF-PrOH-2/25  C; (ii) H 2 N(CHR) m CONH 2 .HCl/Et 3 N/DMF/25  C; (iii) TCEP.HCl/Et 3 N/DMF–H 2 O (9:1)/25  C; (iv) R 0 NCO/DMF/ 25  C; (v) R 0 =CH 2 CH 2 Br, pyridine/under N 2 /25  C. *Corresponding author. Fax: +1-301-496-0222; e-mail: jinman@ niaid.nih.gov