A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability.

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

[1]  M. Wainberg,et al.  Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study. , 2000, International journal of antimicrobial agents.

[2]  C. Thornber,et al.  Isosterism and molecular modification in drug design , 1979 .

[3]  Jun Li,et al.  Directed reductive amination of beta-hydroxy-ketones: convergent assembly of the ritonavir/lopinavir core. , 2007, Organic letters.

[4]  D. Evans,et al.  Selective lithiation of 2-methyloxazoles. Applications to pivotal bond constructions in the phorboxazole nucleus. , 1999, Organic letters.

[5]  M. Lv,et al.  Developments of indoles as anti-HIV-1 inhibitors. , 2009, Current pharmaceutical design.

[6]  M. Poupart,et al.  Reagents for organic synthesis. Part 3. Tin-mediated esterification in macrolide synthesis , 1983 .

[7]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[8]  Christopher A. Lipinski,et al.  Chapter 27. Bioisosterism in Drug Design , 1986 .

[9]  Xiaoqi Chen,et al.  Chapter 32. The use of bioisosteric groups in lead optimization , 2003 .

[10]  J. Wityak,et al.  Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists. , 2010, Journal of medicinal chemistry.

[11]  S. Wain-Hobson,et al.  Anti-termination by SIV Tat requires flexibility of the nascent TAR structure. , 2004, Journal of molecular biology.

[12]  S. Rychnovsky,et al.  Mukaiyama aldol-Prins cyclization cascade reaction: a formal total synthesis of leucascandrolide A. , 2001, Journal of the American Chemical Society.

[13]  J. Yadav,et al.  Vanadium(III) chloride catalyzed Biginelli condensation: solution phase library generation of dihydropyrimidin-(2H)-ones☆ , 2003 .

[14]  S. Kiertiburanakul,et al.  Emerging of HIV drug resistance: epidemiology, diagnosis, treatment and prevention. , 2009, Current HIV research.

[15]  Youcef Mehellou,et al.  Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? , 2010, Journal of medicinal chemistry.

[16]  Klaus Korn,et al.  Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. , 2005, The Journal of infectious diseases.

[17]  C. Holmquist,et al.  A selective method for the direct conversion of aldehydes into .beta.-keto esters with ethyl diazoacetate catalyzed by tin(II) chloride , 1989 .

[18]  E. LaVoie,et al.  Bioisosterism: A Rational Approach in Drug Design. , 1996, Chemical reviews.

[19]  Sung-Jun Han,et al.  Discovery of 3,4-dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV-1 replication. , 2012, Bioorganic & medicinal chemistry letters.

[20]  N. Meanwell.  Synopsis of some recent tactical application of bioisosteres in drug design. , 2011, Journal of medicinal chemistry.

[21]  C. Kappe,et al.  Traceless solid-phase synthesis of bicyclic dihydropyrimidones using multidirectional cyclization cleavage. , 2002, Journal of combinatorial chemistry.

[22]  M. Kazatchkine,et al.  Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy. , 2000, The Journal of infectious diseases.

[23]  M. Rustad,et al.  Synthesis of nitrooxazoles , 1981 .

[24]  D. Dess,et al.  A useful 12-I-5 triacetoxyperiodinane (the Dess-Martin periodinane) for the selective oxidation of primary or secondary alcohols and a variety of related 12-I-5 species , 1991 .