Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections was written by Kumar, Nag S.;Dullaghan, Edie M.;Finlay, B. Brett;Gong, Huansheng;Reiner, Neil E.;Jon Paul Selvam, J.;Thorson, Lisa M.;Campbell, Sara;Vitko, Nicholas;Richardson, Anthony R.;Zoraghi, Roya;Young, Robert N.. And the article was included in Bioorganic & Medicinal Chemistry in 2014.Category: indole-building-block This article mentions the following:
A novel series of bis-indoles derived from naturally occurring marine alkaloid cis-3,4-dihydrohamacanthin B (I) was synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK is not only critical for bacterial survival which would make it a target for development of novel antibiotics, but it is reported to be one of the most highly connected ‘hub proteins’ in MRSA, and thus should be very sensitive to mutations and making it difficult for the bacteria to develop resistance. From the co-crystal structure of I bound to S. aureus PK we were able to identify the pharmacophore needed for activity. Consequently, we prepared simple direct linked bis-indoles such as 6,6′-dibromo-2,2′-biindolyl [II; R, R’ = 6,6′-dibromo (b)] that have similar anti-MRSA activity as compound I. Structure-activity relationship (SAR) studies on II led us to discover more potent compounds such as II [R, R’ = 6,5′-dibromo; 6-bromo-5′-chloro; 5,6,6′-tribromo; 5,6,5′-tribromo (c, d, k, m, resp.)] with enzyme inhibiting activities in the low nanomolar range that effectively inhibited the bacteria growth in culture with min. inhibitory concentrations (MIC) for MRSA as low as 0.5 渭g/mL. Some potent PK inhibitors, such as IIb, exhibited attenuated antibacterial activity and were found to be substrates for an efflux mechanism in S. aureus. Studies comparing a wild type S. aureus with a construct (S. aureus LAC 螖pyk::ErmR) that lacks PK activity confirmed that bactericidal activity of IId was PK-dependant. In the experiment, the researchers used many compounds, for example, (5-Bromo-1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (cas: 475102-13-7Category: indole-building-block).
(5-Bromo-1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (cas: 475102-13-7) belongs to indole derivatives. Indole is an important structural motif of various drugs, therapeutic leads besides its prevalence in numerous natural products, agrochemicals, perfumery, and dyes. It is used in perfumery and in making tryptophan, an essential amino acid, and indoleacetic acid (heteroauxin), a hormone that promotes the development of roots in plant cuttings.Category: indole-building-block
Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles