Chem. have EC50 values towards wild-type HIV-1 near 10 nM and high-nM activities towards the double-variant. The structural expectations from the modeling were much enhanced by obtaining an X-ray crystal structure at 2.88-? resolution for the complex of the parent 2-cyanoindolizine 10b and HIV-1 RT. The aqueous solubilities of the most potent indolizine analogs were also measured to be ca. 40 g/ml, which is similar to that for the approved drug efavirenz and ca. 1000-fold greater than for rilpivirine. INTRODUCTION Inhibitors of HIV-1 reverse transcriptase are central to anti-HIV therapy.1 Though there are five FDA-approved drugs in the non-nucleoside class,2 efavirenz (1) and rilpivirine (2) are particularly important as they are components of the one-a-day combination therapies Atripla and Complera.3 The other two components of the pills are the same, emtricitabine and tenofovir, which are in the nucleoside class of HIV-RT inhibitors. The goal of our research has been to discover new non-nucleoside inhibitors (NNRTIs) that may incorporate advantages for administration, formulation, diminished side effects, and activity towards variant strains of the virus. For example, issues with efavirenz include its daily dosage of 600 mg, poor activity towards HIV-1 variants containing the commonly occurring Lys103Asn (K103N) mutation in RT, and neurological side effects. The situation with rilpivirine is usually curious. Although it has much superior performance in cell-based assays than efavirenz, more virological failure is usually observed for patients using Complera than Atripla. 3,4 Another unusual feature of rilpivirine is usually its extremely low aqueous JAM3 solubility (0.02 g/ml)5 in comparison to the typical range of 4 C Benorylate 4000 g/ml for oral drugs.6 The challenges in developing new NNRTIs that represent an advance over existing compounds are great. One seeks simultaneously compounds that embody high potency towards the wild-type (WT) virus and numerous clinically observed variants, good pharmacological properties including solubility, an absence of structural features that may lead to rapid metabolism, and avoidance of toxicities stemming from reactive functional groups or metabolic products.7,8 A particularly promising class of NNRTIs that we have developed is Benorylate catechol diethers including 3 and 4.9 3 appears to be the most potent Benorylate anti-HIV agent ever reported with an EC50 of 0.055 nM in the standard MT-2 cell assay using wild-type HIV-1. The difluoro analog 4 is also extremely potent at 0.32 nM, has good potency towards variant strains containing the Y181C (16 nM) and K103N/Y181C (85 nM) mutations, and shows low cytotoxicity towards the T-cells (CC50 = 45 M). It was also possible to obtain X-ray crystal structures of 3 and 4 in complex with WT HIV-RT.10 Thus, further structure-based design activities in the catechol diether series have a firm foundation. A structural feature in 3 and 4 as well as in rilpivirine that is addressed here is the cyanovinyl (CV) group. For most medicinal chemists viewing these structures, concern arises that this CV group may be sufficiently electrophilic to act as a Michael Benorylate acceptor leading to potential covalent modification of proteins, nucleic acids, or other biological entities. Though in reality unsaturated nitriles are poor Michael acceptors that require reactive organometallic nucleophiles to undergo conjugate additions,11 the fact is almost no approved drugs contain a cyanovinyl group, and lack of Benorylate precedent is usually often taken as a warning sign in drug discovery. When a search is done for a C=C-CN substructure in a comprehensive file made up of the structures of ca. 1900 approved oral drugs,12 there are just five hits: rilpivirine, entacapone, nilvadipine, teriflunomide, and trilostane. For the latter two examples, the substructure only arises as a tautomer of an -cyanoketone. Rilpivirine is unique in incorporating a simple CV group. By contrast, non-vinyl cyano groups are generally considered to be acceptable in drugs;13 there are 36 examples in the database. Thus, we set out to find a replacement for the cyanovinyl group in the catechol diethers. The prior results exhibited the importance of the CV group to activity.9 The analog of 3 with the CV group truncated to just cyano has an EC50 of 14 nM towards the WT virus, and other compounds with the cyano of the CV group replaced by chlorine, OCH3, or CONH2 showed 100 to 1000-fold losses in activity. These findings are consistent with the modeling and crystallography,9,10 which document.