Design and synthesis of quinolinones as methionyl-tRNA synthetase inhibitors

Farhanullah,; Kim, Su Yeon; Yoon, Eunju; Choi, Eung‐Chil; Kim, Sung Hoon; Kang, Taehee; Samrin, Farhana; Puri, Sadhna; Lee, Jeeyeon

doi:10.1016/j.bmc.2006.06.062

Cited by 22 publications

(14 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…this compound was obtained from 2-amino benzyl alcohol (1 mmol), 2-butyl-4-chloro-1-(4-nitrobenzyl)-1H-imidazole-5-carbaldehyde (1 mmol) and chloro acetic acid (2.5 mmol) in methanol at room temperature as a brown crystalline solid, yield 81%; melting point 53-55°C; elemental analysis calculated for C 22 (23), and 4-(7-chloro-2,4-dihydro-1H-benzo[d] [1,3]oxazin-2-yl)phenol (24) were prepared using the reported protocol.…”

Section: Synthesis Of 2-(2-butyl-mentioning

confidence: 99%

“…Step 2: Preparation of 2-(2-butyl-4-chloro-1-(4-phenoxybenzyl)-1H-imidazol-5-yl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro- [5.5]undecane: this compound was obtained from AA (1 mmol), 2-butyl-4-chloro-1-(4-phenoxybenzyl)-1H-imidazole-5-carbaldehyde (1 mmol), and K 2 CO 3 (2.5 mmol) in methanol as a brown crystalline solid, yield: 84%; melting point: 55-57°C; elemental analysis calculated for C 36 [1,3]oxazine (8). Compound 8 was obtained in two steps.…”

Section: Synthesis Of 2-(mentioning

confidence: 99%

See 1 more Smart Citation

Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Synthesis Of 2-(2-butyl-mentioning

confidence: 99%

Section: Synthesis Of 2-(mentioning

confidence: 99%

Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Inhibitors that target MRSs are already under development against bacterial infections (24). Derivatives of diarylamines, quinolones, urea, and various other lead compounds with potent activities against MRSs have been tested (25)(26)(27). Therefore, we decided to explore various attributes of malarial MRSs with the aim of probing their potential for drug targeting.…”

mentioning

confidence: 99%

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Hussain

Yogavel

Sharma

2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS cyt and PfMRS api . Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS cyt ) or proteobacteria/primitive bacteria (PfMRS api ). We show that PfMRS cyt localizes in parasite cytoplasm, while PfMRS api localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with 35 S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. P lasmodium falciparum is the most virulent form of Plasmodium and a causative agent of malaria. The World Health Organization (WHO) estimates that there are ϳ0.62 million deaths due to malaria per year (1). The P. falciparum genome is AT-rich (81%) and codes for ϳ5,300 proteins, with unusual distributions of several residues (2). Almost 60% of encoded proteins appear to be unique to the parasite, reflecting great evolutionary distance between the parasite and the genomes of known eukaryotes (3). The malaria parasite (and the related apicomplexan Toxoplasma gondii) has three translationally active compartments, i.e., cytoplasm, apicoplasts, and mitochondria (4-8). All malaria parasite proteins involved in the protein synthesis machinery are encoded by the nuclear genome. Either these proteins are transported to target organelles or their modified/activated substrates are transported across the organelles to perform required functions (4-9). The primary enzymes responsible for translating genetic code into polypeptide chains are aminoacyl-tRNA synthetases (aaRSs). The canonical function of aaRSs is to ligate a specific amino acid to its cognate tRNA, which is then employed in protein synthesis. The aaRSs are an ancient class of essential enzymes, and their catalytic domains are conserved in all kingdoms (bacteria, archaebacteria, and eukaryotes). On the basis of catalytic domain architecture, aaRSs are classified into two categories, with each class containing ϳ10 aaRSs (10). Although aaRSs perform the basic function of charging tRNA molecules for protein synthesis, a...

show abstract

“…With the suitable molecular modification and manipulation with possible SAR studies of these compounds, promising anti tubercular agents can be obtained. [26,27].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity

Godge

Kunkulol²

2018

IJCBR

View full text Add to dashboard Cite

In last few decades, though significant progress has been made in the treatment and control strategies of tubercular infections by introducing new diagnostic and monitoring tools and combination therapy, it still continues to be severe problem. The need of study was only because of there are many drugs in market to treat infection but most of the drugs are showing resistance because of the same it is difficult to treat the infection. In this study we chosen quinolone nucleus for study and over it. Thus with the aim of developing novel molecule with improved potency for treating Mycobacterium tuberculosis H37Rv strain infections and with decreased probability of developing drug resistance. Methodology: The synthesis of Quinolone derivatives, starting from substituted aniline and ethyl acetoacetate, by conventional organic reaction and results of investigations of their anti-mycobacterial activity. Results: MICs of the synthesized compounds are compared with existing drugs Cytotoxicity. The substituted quinolones are synthesized by taking mixture of 7-substituted-2-(3-chloro-2-oxopropyl) quinolin-4(1H)-one and different secondary amines. Many compounds have shown promising activity while some were inactive. Conclusion: It was found that Compound A1, A3, B1, B3, have shown promising anti tubercular activity whereas compound A2, A4,B2,B4 were showing moderate anti tubercular activity against std. Streptomycin.

show abstract

Design and synthesis of quinolinones as methionyl-tRNA synthetase inhibitors

Cited by 22 publications

References 11 publications

Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity

Contact Info

Product

Resources

About