Discovery of an HIV integrase inhibitor with an excellent resistance profile

Pryde, David C.; Webster, Rob; Butler, Scott L.; Murray, Edward J.; Whitby, Kevin; Pickford, Chris; Westby, Mike; Palmer, Michael; Bull, D. J.; Vuong, Hannah; Blakemore, David C.; Stead, Darren; Ashcroft, Christopher P.; Gardner, Iain; Bru, Claire; Cheung, WY; Roberts, Ieuan; Morton, Jennifer; Bissell, Richard A.

doi:10.1039/c3md00014a

Cited by 11 publications

(11 citation statements)

References 18 publications

(15 reference statements)

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“…Examples shown in Figure include microbial siderophores (procaryotic matabolites excreted into the extracellular space to scavenge, by chelation, iron needed for growth and differentiation) such as scabichelin ( 1 ), oxachelin ( 2 ), and the simple N ‐hydroxy‐3,4‐dihydroisoquinolin‐1‐one ( 3 ) isolated from Streptomyces griseus . Chelation to the prosthetic zinc ion is the principal mode of action of HIV integrase inhibitors (such as 4 ), matrix metalloprotease inhibitors (exemplified by 5 and 6 ) and histone deacetylase inhibitors (such as 7 ) . However, the in vivo effects of cyclic hydroxamic acids extend beyond those mediated by metal chelation: even classical bacterial siderophores have been shown to exert signaling function, antibacterial activity, and facilitate adaptation to oxidative stress .…”

Section: Figurementioning

confidence: 99%

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Bakulina

Bannykh

Dar’in

et al. 2017

Chemistry A European J

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The first application of multicomponent chemistry (the Castagnoli-Cushman reaction) toward the convenient one-step preparation of cyclic hydroxamic acids is described. Cyclic hydroxamic acids are close analogues of bacterial siderophores (iron-binding compounds) and form stable complexes with Fe ions as confirmed by spectrophotometric measurements. These compounds are potential components for the design of chelating agents for iron overload disease therapy, as well as siderophore-based carrier systems for antibiotic delivery across the bacterial cell wall.

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Section: Figurementioning

confidence: 99%

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Bakulina

Bannykh

Dar’in

et al. 2017

Chemistry A European J

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“…Another analogue PF-4776548 (47b) was identified as a promising candidate with high potency and excellent resistance profiles ( Figure 6) [49]. These studies illustrated a viable protocol to discover IN inhibitors with enhanced potency.…”

Section: -36mentioning

confidence: 98%

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

et al. 2014

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The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.

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“…In further study, a medicinal chemistry strategy was applied that largely retained the naphthyridinone ring system that efficiently coordinated to bound metal ions ( 45a ) while introducing structural changes that can be effective for improving the extent and rate of conjugation of the N -hydroxyl group ( 45b and 45d ), such as steric hindrance of a hydroxyl group and electronic deactivation or removal of this group ( 45c , Figure 21 A). 84 On the basis of these points, substitutions around the dihydronaphthyridinone and benzyl systems were made.…”

Section: Human Immunodeficiency Virus-1 (Hiv-1) and Azaindole-based I...mentioning

confidence: 99%

Development of Azaindole-Based Frameworks as Potential Antiviral Agents and Their Future Perspectives

et al. 2022

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The azaindole (AI) framework continues to play a significant role in the design of new antiviral agents. Modulating the position and isosteric replacement of the nitrogen atom of AI analogs notably influences the intrinsic physicochemical properties of lead compounds. The intra- and intermolecular interactions of AI derivatives with host receptors or viral proteins can also be fine tuned by carefully placing the nitrogen atom in the heterocyclic core. This wide-ranging perspective article focuses on AIs that have considerable utility in drug discovery programs against RNA viruses. The inhibition of influenza A, human immunodeficiency, respiratory syncytial, neurotropic alpha, dengue, ebola, and hepatitis C viruses by AI analogs is extensively reviewed to assess their plausible future potential in antiviral drug discovery. The binding interaction of AIs with the target protein is examined to derive a structural basis for designing new antiviral agents.

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Discovery of an HIV integrase inhibitor with an excellent resistance profile

Cited by 11 publications

References 18 publications

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

Development of Azaindole-Based Frameworks as Potential Antiviral Agents and Their Future Perspectives

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