2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase.

Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold-371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure-activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.

[1]  M. Markowitz,et al.  Goals and milestones during treatment of HIV-1 infection with antiretroviral therapy: a pathogenesis-based perspective. , 2002, Antiviral research.

[2]  Christophe Meyer,et al.  Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. , 2005, Journal of medicinal chemistry.

[3]  Ming Hao,et al.  Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y12 Antagonists for Inhibition of Platelet Aggregation , 2011, J. Chem. Inf. Model..

[4]  Wei Huang,et al.  Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase--structure-activity relationships and crystallographic analysis. , 2008, Bioorganic & medicinal chemistry letters.

[5]  M. Polis,et al.  Drug interactions in patients infected with human immunodeficiency virus. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  P. Harrigan,et al.  2004: which HIV-1 drug resistance mutations are common in clinical practice? , 2004, AIDS reviews.

[7]  S. Sivan,et al.  Multiple receptor conformation docking and dock pose clustering as tool for CoMFA and CoMSIA analysis – a case study on HIV-1 protease inhibitors , 2012, Journal of Molecular Modeling.

[8]  Y. Cao,et al.  HIV-1 drug resistance in newly infected individuals. , 1999, JAMA.

[9]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[10]  S. Sigurdsson,et al.  Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. , 2002, European journal of biochemistry.

[11]  J. Kaldor,et al.  HIV disease progression in Australia in the time of combination antiretroviral therapies , 1998, The Medical journal of Australia.

[12]  D O Morgan,et al.  Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity , 1995, Journal of virology.

[13]  S. Wold,et al.  The Collinearity Problem in Linear Regression. The Partial Least Squares (PLS) Approach to Generalized Inverses , 1984 .

[14]  3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non-nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses , 2011, Journal of molecular modeling.

[15]  Michael Nilges,et al.  Comparative Evaluation of 3D Virtual Ligand Screening Methods: Impact of the Molecular Alignment on Enrichment , 2010, J. Chem. Inf. Model..

[16]  J. Chermann,et al.  Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). , 1983, Science.

[17]  James M. Chen,et al.  N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2010, Bioorganic & medicinal chemistry letters.

[18]  D. E. Patterson,et al.  Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies , 1988 .

[19]  E. Clercq,et al.  Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. , 2009, International journal of antimicrobial agents.

[20]  R. Connor,et al.  Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. , 1995, Virology.

[21]  P. Bates,et al.  Analysis of the subgroup A avian sarcoma and leukosis virus receptor: the 40-residue, cysteine-rich, low-density lipoprotein receptor repeat motif of Tva is sufficient to mediate viral entry , 1995, Journal of virology.

[22]  I. Mcnicholl,et al.  Etravirine and Rilpivirine: Nonnucleoside Reverse Transcriptase Inhibitors with Activity Against Human Immunodeficiency Virus Type 1 Strains Resistant to Previous Nonnucleoside Agents , 2009, Pharmacotherapy.

[23]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[24]  D I Stuart,et al.  Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants. , 1999, Journal of medicinal chemistry.

[25]  P. Geladi.  Notes on the history and nature of partial least squares (PLS) modelling , 1988 .

[26]  Johann Gasteiger,et al.  Multivariate structure‐activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: The PLS method , 1984 .

[27]  J Leibowitch,et al.  Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). , 1983, Science.

[28]  M. Nelson,et al.  Non-nucleoside reverse transcriptase inhibitors—an overview , 2003, International journal of STD & AIDS.