Rational design, synthesis and evaluation of novel-substituted 1,2,3-triazolylmethyl carbazoles as potent inhibitors of Mycobacterium tuberculosis

Surineni, Goverdhan; Yogeeswari, Perumal; Sriram, Dharmarajan; Kantevari, Srinivas

doi:10.1007/s00044-014-1210-y

Cited by 29 publications

(19 citation statements)

References 35 publications

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“…Several natural and synthetic indolocarbazole alkaloids such as staurosporine [39,[50][51][52][53], arcyriaflavins [34,54], ED-110 [35], rebeccamycin [32,55], and related analogues have been widely studied for their antibacterial [39,56], anti-tubercular [39,57], antifungal [56], anticancer [35,58,59], cytotoxic activities [60], as well as inhibition against human African trypanosomiasis (HAT) [52,61]. In fact, a number of these analogues, UCN-01 [62], BMY-27557 [63], XL119 [64], NSC 655,649 [39,40], have already entered clinical trials.…”

Section: Biological Activity Testmentioning

confidence: 99%

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

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Whole-genome sequence data of the genus Streptomyces have shown a far greater chemical diversity of metabolites than what have been discovered under typical laboratory fermentation conditions. In our previous natural product discovery efforts on Streptomyces sp. MA37, a bacterium isolated from the rhizosphere soil sample in Legon, Ghana, we discovered a handful of specialised metabolites from this talented strain. However, analysis of the draft genome of MA37 suggested that most of the encoded biosynthetic gene clusters (BGCs) remained cryptic or silent, and only a small fraction of BGCs for the production of specialised metabolites were expressed when cultured in our laboratory conditions. In order to induce the expression of the seemingly silent BGCs, we have carried out a co-culture experiment by growing the MA37 strain with the Gram-negative bacterium Pseudomonas sp. in a co-culture chamber that allows co-fermentation of two microorganisms with no direct contact but allows exchange of nutrients, metabolites, and other chemical cues. This co-culture approach led to the upregulation of several metabolites that were not previously observed in the monocultures of each strain. Moreover, the co-culture induced the expression of the cryptic indole alkaloid BGC in MA37 and led to the characterization of the known indolocarbazole alkaloid, BE-13793C 1. Neither bacterium produced compound 1 when cultured alone. The structure of 1 was elucidated by Nuclear Magnetic Resonance (NMR), mass spectrometry analyses and comparison of experimental with literature data. A putative biosynthetic pathway of 1 was proposed. Furthermore, BE-13793C 1 showed strong anti-proliferative activity against HT-29 (ATCC HTB-38) cells but no toxic effect to normal lung (ATCC CCL-171) cells. To the best of our knowledge, this is the first report for the activity of 1 against HT-29. No significant antimicrobial and anti-trypanosomal activities for 1 were observed. This research provides a solid foundation for the fact that a co-culture approach paves the way for increasing the chemical diversity of strain MA37. Further characterization of other upregulated metabolites in this strain is currently ongoing in our laboratory.

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Section: Biological Activity Testmentioning

confidence: 99%

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

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“…To the best of our knowledge, most of the synthesized compounds are new except 6a [29], 9a, and 9e [30]. All the synthesized compounds were characterized by spectroscopic techniques like IR, 1 H NMR, 13 C NMR, mass spectrometry and screened in vitro for antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus niger.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial evaluation of 1,4-disubstituted 1,2,3-triazoles containing benzofused N-heteroaromatic moieties

et al. 2015

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“…Due to this approach, two bioactive pharmacophores are conjugated through a spacer into a single structure to behave as dual-acting drugs and/or to lessen the side effects [19,20]. Carbazole-triazole hybrid molecules have found extensive applications in the design and synthesis of many carbazole-triazole hybrid-based drugs, drug candidates [21][22][23][24][25][26] and optoelectronic devices [27][28][29][30]. To this end, the carbazole-triazole hybrid moieties have been widely applied in scaffolds of many molecules exhibiting diverse pharmaceutical properties.…”

Section: Introductionmentioning

confidence: 99%

“…3) [25,26,31,32]. Therefore, with inspiration from the remarkable biological activities of 1,2,3-triazole and carbazole and also in continuation of our interest in discovering the new azole bioactive compounds [33][34][35][36][37][38][39][40], herein we would like to report the design and synthesis of some 1,2,3-triazolyl β-hydroxy alkyl/carbazole hybrids as a new type of antifungal agent (Fig.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl $$\upbeta $$ β -hydroxy alkyl/carbazole hybrid molecules

Rad

Behrouz

et al. 2016

Mol Divers

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The design, synthesis and biological study of several novel 1,2,3-triazolyl [Formula: see text]-hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The 'Click' Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse [Formula: see text]-azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between [Formula: see text]-hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a-10n as potential lead antifungal agents for future investigations.

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Rational design, synthesis and evaluation of novel-substituted 1,2,3-triazolylmethyl carbazoles as potent inhibitors of Mycobacterium tuberculosis

Cited by 29 publications

References 35 publications

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

Synthesis and antimicrobial evaluation of 1,4-disubstituted 1,2,3-triazoles containing benzofused N-heteroaromatic moieties

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl $$\upbeta $$ β -hydroxy alkyl/carbazole hybrid molecules

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