Novel Indazole Non-Nucleoside Reverse Transcriptase Inhibitors Using Molecular Hybridization Based on Crystallographic Overlays

Jones, Lyn H.; Allan, Gill; Barba, Oscar; Burt, Catherine; Corbau, Romuald; Dupont, Thomas; Knöchel, Thorsten; Irving, S.L.; Middleton, Donald S.; Mowbray, Charles E.; Perros, Manos; Ringrose, H.; Swain, Nigel A.; Webster, Robert O.; Westby, Mike; Phillips, Chris

doi:10.1021/jm801322h

Cited by 47 publications

(32 citation statements)

References 20 publications

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“…Heterodimeric wt and K103N HIV-1 RT were expressed and purified as described previously (28) and crystallized in the presence of lersivirine. The crystals belong to space group C222 1 (unit cell dimensions: a Ϸ 117 Å, b Ϸ 154 Å, and c Ϸ 155 Å) and are isomorphous with those reported previously (24). X-ray diffraction data, to 2.8 Å and 3.2 Å resolution, were collected at 100 K with an ADSC Quantum 4 CCD detector at Station 14.2 of SRS, Daresbury, United Kingdom, and "in house" using a Rigaku FRD generator and Saturn92 detector.…”

supporting

confidence: 55%

Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

Corbau¹,

Mori²,

Phillips

et al. 2010

Antimicrob Agents Chemother

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The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC 50 s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.

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supporting

confidence: 55%

Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

Corbau¹,

Mori²,

Phillips

et al. 2010

Antimicrob Agents Chemother

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“…For the pharmacological and biochemical properties of substituted indazoles, see: Saczewski et al (2008); Jones et al (2009); Bouissane et al (2006). For compounds with similar structures, see: El Brahmi et al (2009Brahmi et al ( , 2011.…”

Section: Related Literaturementioning

confidence: 99%

“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al 2008); software used to prepare material for publication: PLATON (Spek, 2009) and publCIF (Westrip, 2010 Indazole derivatives constitute an exciting heterocyclic family because of their important biological activities. Thus substituted indazoles are generally found to be of pharmaceutical interest in a variety of therapeutic areas (Saczewski et al, 2008, Jones et al, 2009 and with significant cytotoxicities against human (colon and prostate) and murine (leukemia) cell lines (Bouissane et al, 2006).…”

Section: Data Collectionmentioning

confidence: 99%

1-Allyl-6-nitro-1H-indazole

Brahmi¹,

Benchidmi²,

Essassi³

et al. 2012

Acta Cryst E

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The fused five- and six-membered rings in the title molecule, C10H9N3O2, are essentially coplanar, the largest deviation from the mean plane being 0.012 (1) Å for the C atom linked to the nitro group. The fused-ring system makes a dihedral angle of 11.34 (6)° with the nitro group, leading to a syn-periplanar conformation. The plane through the atoms forming the allyl group is nearly perpendicular to the indazole fused-ring system, as indicated by the dihedral angle of 73.3 (5)°. In the crystal, each molecule is linked to its symmetry equivalent about the center of inversion by pairs of non-classical C—H⋯O hydrogen bonds, forming an extended tape motif parallel to the (-12-1) plane.

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“…A major problem associated with NNRTIs for the treatment of HIV is their lack of flexibility to mutations in the RT enzyme. Jones et al 81 . have created a novel series of indazole NNRTIs (Fig.…”

Section: Antiviralsmentioning

confidence: 99%

“… Top: molecular hybridization of capravirine and efavirenz to create the indazole template; bottom: crystallographic overlay of efavirenz (gold) and capravirine (pink) 81 . (In color in Annals online.)…”

Section: Antiviralsmentioning

confidence: 99%

Structure‐based design of anti‐infectives

Agarwal

Fishwick

2010

Annals of the New York Academy of Sciences

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Infectious diseases, caused by bacteria, viruses, fungi, protozoa, or parasites are among the leading causes of death worldwide. The efficacy of all current anti-infectives is threatened by the spread of drug resistance factors, with some already made ineffective, and, as a result, there is a pressing need for a new pipeline of robust anti-infective drugs. In silico approaches, such as virtual high throughput screening and de novo structure-based rational drug design, have been established as powerful tools in drug discovery. In this review, we explore the exciting opportunities for antimalarial, antiviral, and antibacterial drug discovery arising from the new paradigm of structure-based drug design.

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Novel Indazole Non-Nucleoside Reverse Transcriptase Inhibitors Using Molecular Hybridization Based on Crystallographic Overlays

Cited by 47 publications

References 20 publications

Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

1-Allyl-6-nitro-1H-indazole

Structure‐based design of anti‐infectives

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