Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Govender, Preshendren; Müller, Rudolf; Singh, K. Chandramani; Reddy, Virsinha; Eyermann, Charles J.; Fienberg, Stephen; Ghorpade, Sandeep R.; Koekemoer, L.; Myrick, Alissa; Schnappinger, Dirk; Engelhart, Curtis A.; Jaclynn, Meshanni,; Byl, Jo Ann W.; Osheroff, Neil; Singh, Vinayak; Chibale, Kelly; Basarab, Gregory S.

doi:10.1021/acs.jmedchem.2c00266

Cited by 24 publications

(54 citation statements)

References 48 publications

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“…In particular, when examining the substrate spectrum, N-methyloxindole was found to be inferior to the stereoselectivity. According to experimental results, the α,βunsaturated aldehyde undergoes a double-Michael addition reaction to produce an adduct, which in turn undergoes an intramolecular aldol condensation reaction followed by a dehydration step to produce enantioselective spirooxindoles and their derivatives (16). He, Wang, Peng, and co-workers developed drug-like cyclohexane-fused spirocyclic scaffolds (17) with six consecutive stereogenic centers by a reaction of a chiral γ-nitroaldehyde with various unsaturated pyrazolones, Scheme 11.…”

Section: Michael-michael-aldol Cascade Reactionsmentioning

confidence: 99%

“…[11] Enantioenriched spiro derivatives [12] are characterized by the interesting fusion of two molecular rings linked by a common tetrasubstituted stereogenic center. They are an important component of several natural products, [13][14][15] bioactive compounds, [16][17][18][19][20] and find applications in asymmetric catalysis, [21][22][23][24] thermally stable OLED, [25][26][27][28][29][30][31] sensing, [32][33][34][35][36] and HMT (hole-transporting material). [37][38][39][40][41][42][43][44][45][46] Compared with singly condensed heterocycles spiro-hetero/carbocycles have the obvious advantage of structural compactness, which reduces lipophilicity.…”

Section: Introductionmentioning

confidence: 99%

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Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Patel

2022

Eur J Org Chem

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Spiro derivatives are important scaffolding substances found in many natural products and pharmaceuticals. In the last decade, numerous new approaches based on multicomponent reactions have been explored for the selective and efficient development of new spiro derivatives using various organocatalytic and transition metal‐based catalytic systems. This Review discusses pioneering advances in the field of catalytic stereoselective multicomponent reactions for the preparation of various spiro derivatives. These include stereoselective Michael cascade cyclization reactions, cycloadditions, diastereoselective reactions, and miscellaneous reactions for the synthesis of spiro‐hetero/carbocycles. Advances in the last decade have made it possible to synthesize various spiro compounds with good to excellent stereoselectivity under appropriate reaction conditions. However, achieving high regioselectivity in several described multicomponent reactions remains a challenge. Organocatalysts and transition‐metal‐based catalysts play a crucial role in achieving this milestone. Proposed catalytic mechanisms and supporting evidence are highlighted in this Review. The progress described in catalytic stereoselective approaches for spiro derivatives is immense. However, it is expected that new stereoselective synthetic methods will soon be developed that can be widely used for the preparation of spiro‐heterocycles/carbocycles.

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Section: Michael-michael-aldol Cascade Reactionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Patel

2022

Eur J Org Chem

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“…Significant efforts, including target-based screens have resulted in new antibacterial drugs that are effective against fluoroquinolone-resistant pathogens. These include Spiropyrimidinetriones which act against type II topoisomerase ( Basarab et al., 2022 ; Govender et al., 2022 ) as well as compounds inhibiting DNA replication with different modes of action like the aminobenzimidazole, VXc-486, alias SPR720 ( Locher et al., 2015 ); Thiazolopyridone ureas ( Kale et al., 2014 ) and more recently, Gepotidacin analogs, members of the “novel bacterial topoisomerase inhibitors” (NBTIs) ( Blanco et al., 2015 ; Gibson et al., 2018 ). As deeply reviewed by Reiche et al.…”

Section: Approaches To Address Highly Validated Drugs and Targets Com...mentioning

confidence: 99%

“Upcycling” known molecules and targets for drug-resistant TB

Roubert

Fontaine²,

Upton³

2022

Front. Cell. Infect. Microbiol.

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Despite reinvigorated efforts in Tuberculosis (TB) drug discovery over the past 20 years, relatively few new drugs and candidates have emerged with clear utility against drug resistant TB. Over the same period, significant technological advances and learnings around target value have taken place. This has offered opportunities to re-assess the potential for optimization of previously discovered chemical matter against Mycobacterium tuberculosis (M.tb) and for reconsideration of clinically validated targets encumbered by drug resistance. A re-assessment of discarded compounds and programs from the “golden age of antibiotics” has yielded new scaffolds and targets against TB and uncovered classes, for example beta-lactams, with previously unappreciated utility for TB. Leveraging validated classes and targets has also met with success: booster technologies and efforts to thwart efflux have improved the potential of ethionamide and spectinomycin classes. Multiple programs to rescue high value targets while avoiding cross-resistance are making progress. These attempts to make the most of known classes, drugs and targets complement efforts to discover new chemical matter against novel targets, enhancing the chances of success of discovering effective novel regimens against drug-resistant TB.

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“…Even if this compound was also effective in vivo, many synthesis and evaluation iterations were undertaken at Astra Zeneca to reach, in 2014, zoliflodacin (12) [124] which is currently undergoing a phase 3 clinical trial, sponsored by Entasis Therapeutics [125]. Interestingly, further synthetic work is going on [126,127], including on original analogues active in vivo against Mycobacterium tuberculosis [128]. Of note is that in 2011, Astra Zeneca undertook some rather extensive strategic changes which led to an improvement of the drug discovery productivity and, possibly, to zoliflodacin (12) [129].…”

Section: Hit To Lead Recent Success Stories In Antibacterialsmentioning

confidence: 99%

On drug discovery against infectious diseases and academic medicinal chemistry contributions

Janin¹

2022

Beilstein J. Org. Chem.

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This perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns.

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Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Cited by 24 publications

References 48 publications

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

“Upcycling” known molecules and targets for drug-resistant TB

On drug discovery against infectious diseases and academic medicinal chemistry contributions

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