Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase

Talukdar, Arindam; Morgunova, Ekaterina; Duan, Jian‐Xin; Meining, Winfried; Foloppe, Nicolas; Nilsson, Lennart; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Ladenstein, Rudolf; Cushman, Mary

doi:10.1016/j.bmc.2010.03.072

Cited by 21 publications

(23 citation statements)

References 65 publications

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“…41,42,48,51,52 The crystal structure of 75 bound to M. tuberculosis lumazine synthase (PDB code: 2C97) 41 encouraged the synthesis of compound 78 , which is described in Scheme 10.…”

Section: Resultsmentioning

confidence: 99%

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O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

Talukdar

Zhao

et al. 2012

J. Org. Chem.

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Lumazine synthase catalyzes the penultimate step in the biosynthesis of riboflavin, while riboflavin synthase catalyzes the last step. O-Nucleoside, S-nucleoside, and N-nucleoside analogues of hypothetical lumazine biosynthetic intermediates have been synthesized in order to obtain structure and mechanism probes of these two enzymes, as well as inhibitors of potential value as antibiotics. Methods were devised for the selective cleavage of benzyl protecting groups in the presence of other easily reduced functionality by controlled hydrogenolysis over Lindlar catalyst. The deprotection reaction was performed in the presence of other reactive functionality including nitro groups, alkenes, and halogens. The target compounds were tested as inhibitors of lumazine synthase and riboflavin synthase obtained from a variety of microorganisms. In general, the S-nucleosides and N-nucleosides were more potent than the corresponding O-nucleosides as lumazine synthase and riboflavin synthase inhibitors, while the C-nucleosides were the least potent. A series of molecular dynamics simulations followed by free energy calculations using the Poisson–Boltzmann/surface area (MM-PBSA) method were carried out in order to rationalize the results of ligand binding to lumazine synthase, and the results provide insight into the dynamics of ligand binding as well as the molecular forces stabilizing the intermediates in the enzyme-catalyzed reaction.

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“…41,42,48,51,52 The crystal structure of 75 bound to M. tuberculosis lumazine synthase (PDB code: 2C97) 41 encouraged the synthesis of compound 78 , which is described in Scheme 10.…”

Section: Resultsmentioning

confidence: 99%

“…Intermediate 80 was obtained by the reaction of 79 52 with methacrolyl chloride. The chloride and double bond present in the intermediate 80 prevented the application of general hydrogenolysis deprotection protocol using Pd/C.…”

Section: Resultsmentioning

confidence: 99%

O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

Talukdar

Zhao

et al. 2012

J. Org. Chem.

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“…Diethyl aminoalkylphosphonates 2a-2d (aminomethyl-, 2-aminoethyl-, 3-aminopropyl-, and 4-aminobutylphosphonates), used in this study, are known and have already been described in the literature [19][20][21][22][23][24][25][26][27]. Thus, diethyl aminomethylphosphonate (2a) was prepared in total 90 % yield from N-(bromomethyl)phthalimide followed by the treatment with hydrazine [19][20][21] whereas xaminoalkylphosphonates 2b-2d were synthesized from the corresponding x-azidoalkylphosphonates 1b-1d [28][29][30][31][32] by catalytic hydrogenation [23,26].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, antiviral, cytotoxic and cytostatic evaluation of N 1-(phosphonoalkyl)uracil derivatives

et al. 2016

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A series of N 1 -(phosphonoalkyl)uracils was prepared in a two-step reaction sequence from xaminoalkylphosphonates and (E)-3-ethoxyacryloyl isocyanate followed by the uracil ring closure. Under standard conditions (NCS; NBS; I 2 /CAN) all N 1 -(phosphonoalkyl)uracils were transformed into the respective 5-halogeno derivatives to be later benzoylated at N3. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses. One compound was slightly active against human cytomegalovirus in HEL cell cultures (EC 50 = 45 lM) while another showed weak activity against varicella-zoster virus (TK ? VZV strain OKA and TK -VZV strain 07-1) with EC 50 = 43 and 53 lM, respectively. In addition, several compounds exhibited noticeable inhibitory effects on the proliferation of human cervical carcinoma cells (HeLa) at a concentration lower than 200 lM. Graphical abstract

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“…The library of drug‐like molecules was screened through various predetermined filters. Docking analysis of the selected structures into the LS active site led to an interesting new class of compound, 107 , with a benzindolone scaffold . The new scaffold has great potential for drug development because it has a sulfonamide moiety, which is present in many antibacterial drugs.…”

Section: Virtual Screeningmentioning

confidence: 99%

“…Docking analysis of the selected structures into the LS active site led to an interesting new class of compound, 107, with a benzindolone scaffold. 76 The new scaffold has great potential for drug development because it has a sulfonamide moiety, which is present in many antibacterial drugs. Benzindolone derivative 107 displayed a K i of 70 µM against M. tuberculosis LS.…”

Section: Virtual Screeningmentioning

confidence: 99%

Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents

Kundu

Sarkar

Ray

et al. 2019

Medicinal Research Reviews

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Life on earth depends on the biosynthesis of riboflavin, which plays a vital role in biological electron transport processes. Higher mammals obtain riboflavin from dietary sources; however, various microorganisms, including Gram‐negative pathogenic bacteria and yeast, lack an efficient riboflavin‐uptake system and are dependent on endogenous riboflavin biosynthesis. Consequently, the inhibition of enzymes in the riboflavin biosynthesis pathway would allow selective toxicity to a pathogen and not the host. Thus, the riboflavin biosynthesis pathway is an attractive target for designing novel antimicrobial drugs, which are urgently needed to address the issue of multidrug resistance seen in various pathogens. The enzymes involved in riboflavin biosynthesis are lumazine synthase (LS) and riboflavin synthase (RS). Understanding the details of the mechanisms of the enzyme‐catalyzed reactions and the structural changes that occur in the enzyme active sites during catalysis can facilitate the design and synthesis of suitable analogs that can specifically inhibit the relevant enzymes and stop the generation of riboflavin in pathogenic bacteria. The present review is the first compilation of the work that has been carried out over the last 25 years focusing on the design of inhibitors of the biosynthesis of riboflavin based on an understanding of the mechanisms of LS and RS. This review aimed to address the fundamental advances in our understanding of riboflavin biosynthesis as applied to the rational design of a novel class of inhibitors. These advances have been aided by X‐ray structures of ligand‐enzyme complexes, rotational‐echo, double‐resonance nuclear magnetic resonance spectroscopy, high‐throughput screening, virtual screenings, and various mechanistic probes.

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Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase

Cited by 21 publications

References 65 publications

O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

Synthesis, antiviral, cytotoxic and cytostatic evaluation of N 1-(phosphonoalkyl)uracil derivatives

Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents

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