With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o, o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o, o-difluoro- p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.

Gilead Sciences Inc Foster City USA

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic

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World Health Organization, Geneva, Switzerland. www.who.int (accessed 4 September 2018).

Poorolajal J, Hooshmand E, Mahjub H, et al. Survival rate of AIDS disease and mortality in HIV-infected patients: a meta-analysis. Public Health 2016; 139: 3–12. PubMed

De Clercq E. Non‐nucleoside reverse transcriptase inhibitors (NNRTIs). Past Present and Future Chem Biodivers 2004; 1: 44–64. PubMed

Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 29–38. PubMed

Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 39–48. PubMed

Geretti AM. Shifting paradigms: the resistance profile of etravirine. J Antimicrob Chemother 2008; 62: 643–647. PubMed

Janssen PA, Lewi PJ, Arnold E, et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1 E)-2-cyanoethenyl]-2, 6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile (R278474, rilpivirine). J Med Chem 2005; 48: 1901–1909. PubMed

Baert L, van G, Klooster T, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm 2009; 72: 502–508. PubMed

de Béthune M-P. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 2010; 85: 75–90. PubMed

Reynolds C, de Koning CB, Pelly SC, et al. In search of a treatment for HIV–current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Chem Soc Rev 2012; 41: 4657–4670. PubMed

De Clercq E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 1998; 38: 153–179. PubMed

Zhan P, Chen X, Li D.et al. HIV‐1 NNRTIs: structural diversity, pharmacophore similarity, and impliations for drug design. Med Res Rev 2013; 33: E1–72. PubMed

Lansdon EB, Brendza KM, Hung M, et al. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J Med Chem 2010; 53: 4295–4299. PubMed

Li D, Zhan P, De Clercq E, et al. Strategies for the design of HIV-1 non-nucleoside reverse transcriptase inhibitors: lessons from the development of seven representative paradigms. J Med Chem 2012; 55: 3595–3613. PubMed

Zhan P, Pannecouque C, De Clercq E, et al. Anti-HIV drug discovery and development: current innovations and future trends: miniperspective. J Med Chem 2015; 59: 2849–2878. PubMed

Chen FE, Zeng Z-S, Liang Y-H. Feng, Patent CN 101723903, P.R.C. Fudan University, China, 2010.

Ma XD, Yang SQ, Gu SX, et al. Synthesis and anti‐HIV activity of Aryl‐2‐[(4‐cyanophenyl) amino]‐4‐pyrimidinone hydrazones as potent non‐nucleoside reverse transcriptase inhibitors. ChemMedChem 2011; 6: 2225–2232. PubMed

Feng X-Q, Zeng Z-S, Liang Y-H, et al. Synthesis and biological evaluation of 4-(hydroxyimino) arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV. Bioorg Med Chem 2010; 18: 2370–2374. PubMed

Liu Y, Meng G, Zheng A, et al. Design and synthesis of a new series of cyclopropylamino-linking diarylpyrimidines as HIV non-nucleoside reverse transcriptase inhibitors. Eur J Pharm Sci 2014; 62: 334–341. PubMed

Meng G, Liu Y, Zheng A, et al. Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors. Eur J Med Chem 2014; 82: 600–611. PubMed

Yan Z-H, Wu H-Q, Chen W-X, et al. Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem 2014; 22: 3220–3226. PubMed

Zeng ZS, Liang YH, Feng XQ, et al. Lead optimization of diarylpyrimidines as non‐nucleoside inhibitors of HIV‐1 reverse transcriptase. ChemMedChem 2010; 5: 837–840. PubMed

Gu S-X, He Q-Q, Yang S-Q, et al. Synthesis and structure–activity relationship of novel diarylpyrimidines with hydromethyl linker (CH (OH)-DAPYs) as HIV-1 NNRTIs. Bioorg Med Chem 2011; 19: 5117–5124. PubMed

Yan Z-H, Huang X-Y, Wu H-Q, et al. Structural modifications of CH (OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem 2014; 22: 2535–2541. PubMed

Gu S-X, Qiao H, Zhu Y-Y, et al. A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: design, synthesis and anti-HIV activities. Bioorg Med Chem 2015; 23: 6587–6593. PubMed

Šimon P, Baszczyňski O, Šaman D, et al. Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1. Eur J Med Chem 2016; 122: 185–195. PubMed

Mordant C, Schmitt B, Pasquier E, et al. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur J Med Chem 2007; 42: 567–579. PubMed

Rotili D, Tarantino D, Artico M, et al. Diarylpyrimidine−dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level. J Med Chem 2011; 54: 3091–3096. PubMed

Ludovici DW, De Corte BL, Kukla MJ, et al. Evolution of anti-HIV drug candidates. Part 3: diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001; 11: 2235–2239. PubMed

Bedford ST, Benwell KR, Brooks T, et al. of potent and selective functional antagonists of the human adenosine A 2B receptor. Bioorg Med Chem Lett 2009; 19: 5945–5949. PubMed

Miyashita A, Matsuda H, Iijima C, et al. Catalytic action of azolium salts. ii. aroylation of 4-chloroquinazolines with aromatic aldehydes catalyzed by 1, 3-dimethylbenzimidazolium iodide. Chem Pharm Bull 1992; 40: 43–48.

Procházková E, Čechová L, Tarábek J, et al. Tunable push–pull interactions in 5-nitrosopyrimidines. J Org Chem 2016; 81: 3780–3789. PubMed

Surry DS, Buchwald SL. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem Sci 2011; 2: 27–50. PubMed PMC

Cantrell AS, Engelhardt P, Högberg M, et al. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure−activity relationship studies of PETT analogs. J Med Chem 1996; 39: 4261–4274. PubMed

Chen X, Liu X, Meng Q, et al. Novel piperidinylamino-diarylpyrimidine derivatives with dual structural conformations as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem Lett 2013; 23: 6593–6597. PubMed

Joshi S, Maikap GC, Titirmare S, et al. An improved synthesis of etravirine. Org Process Res Dev 2010; 14: 657–660.

Thrippleton MJ, Keeler J. Elimination of zero‐quantum interference in two‐dimensional NMR spectra. Angew Chem 2003; 115: 4068–4071. PubMed

Pauwels R, De Clercq E, Desmyter J.et al. Sensitive and rapid assay on MT-4 cells for detection of antiviral compounds against the AIDS virus. J Virol Methods 1987; 16: 171–185. PubMed

Andries K, Azijn H, Thielemans T.et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48: 4680–4686. PubMed PMC

Janssen PA, Lewi PJ, Arnold E.et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1 E)-2-cyanoethenyl]-2, 6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile (R278474, rilpivirine). J Med Chem 2005; 48: 1901–1909. PubMed

Kertesz DJ, Brotherton-Pleiss C, Yang M, et al. Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg Med Chem Lett 2010; 20: 4215–4218. PubMed