Design and synthesis of 11α-substituted bile acid derivatives as potential anti-tuberculosis agents

Pore, Vandana S.; Divse, Jaisingh M.; Charolkar, Chaitanya R.; Nawale, Laxman; Khedkar, Vijay M.; Sarkar, Dhiman

doi:10.1016/j.bmcl.2015.08.006

Cited by 20 publications

(10 citation statements)

References 62 publications

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“…Recently, anticancer drugs were attached to the side chain of DC and mixed with phospholipids . BSs were also substituted into C-11 with antituberculosis agents . Cisplatin-based derivatives showed potential cytotoxic activity in conjugation with metallic nanoparticles. , It is worth mentioning that numerous BSs show unexpected medicinal properties when substituted with specific moieties.…”

Section: Applicationsmentioning

confidence: 99%

“…Cisplatin-based derivatives showed potential cytotoxic activity in conjugation with metallic nanoparticles. , It is worth mentioning that numerous BSs show unexpected medicinal properties when substituted with specific moieties. For examples, BSDs presenting polyaminocarboxylate or aromatic/heteroaromatic amides linked via amino acids on the lateral chain were tested as anticancer agents; N -alkyl and N -acyl derivatives of C-11 amino bile acid esters were shown to inhibit Mycobacterium tuberculosis ; and numerous examples of antimicrobial systems were also reported …”

Section: Applicationsmentioning

confidence: 99%

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Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles

et al. 2018

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Bile salts (BSs) are naturally occurring rigid surfactants with a steroidal skeleton and specific self-assembly and interface behaviors. Using bile salts as precursors, derivatives can be synthesized to obtain molecules with specific functionalities and amphiphilic structure. Modifications on single molecules are normally performed by substituting the least-hindered hydroxyl group on carbon C-3 of the steroidal A ring or at the end of the lateral chain. This leads to monosteroidal rigid building blocks that are often able to self-organize into 1D structures such as tubules, twisted ribbons, and fibrils with helical supramolecular packing. Tubular aggregates are of particular interest, and they are characterized by cross-section inner diameters spanning a wide range of values (3−500 nm). They can form through appealing pH-or temperature-responsive aggregation and in mixtures of bile salt derivatives to provide mixed tubules with tunable charge and size. Other derivatives can be prepared by covalently linking two or more bile salt molecules to provide complex systems such as oligomers, dendrimers, and polymeric materials. The unconventional amphiphilic molecular structure imparts specific features to BSs and derivatives that can be exploited in the formulation of capsules, drug carriers, dispersants, and templates for the synthesis of nanomaterials.

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Section: Applicationsmentioning

confidence: 99%

Section: Applicationsmentioning

confidence: 99%

Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles

et al. 2018

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“…tuberculosis [ 27 ]. Bile acid derivatives are also potential anti-TB agents [ 28 ], and purine metabolism in M . tuberculosis is a target for drug development [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, some bile acids inhibit the in vitro growth of M. tuberculosis [27]. Bile acid derivatives are also potential anti-TB agents [28], and purine metabolism in M. tuberculosis is a target for drug development [29,30]. Furthermore, together with lipid metabolism, these pathways are reportedly linked to anti-TB druginduced hepatotoxicity [31].…”

Section: Plos Onementioning

confidence: 99%

Molecular perturbations in pulmonary tuberculosis patients identified by pathway-level analysis of plasma metabolic features

et al. 2022

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Insight into the metabolic biosignature of tuberculosis (TB) may inform clinical care, reduce adverse effects, and facilitate metabolism-informed therapeutic development. However, studies often yield inconsistent findings regarding the metabolic profiles of TB. Herein, we conducted an untargeted metabolomics study using plasma from 63 Korean TB patients and 50 controls. Metabolic features were integrated with the data of another cohort from China (35 TB patients and 35 controls) for a global functional meta-analysis. Specifically, all features were matched to a known biological network to identify potential endogenous metabolites. Next, a pathway-level gene set enrichment analysis-based analysis was conducted for each study and the resulting p-values from the pathways of two studies were combined. The meta-analysis revealed both known metabolic alterations and novel processes. For instance, retinol metabolism and cholecalciferol metabolism, which are associated with TB risk and outcome, were altered in plasma from TB patients; proinflammatory lipid mediators were significantly enriched. Furthermore, metabolic processes linked to the innate immune responses and possible interactions between the host and the bacillus showed altered signals. In conclusion, our proof-of-concept study indicated that a pathway-level meta-analysis directly from metabolic features enables accurate interpretation of TB molecular profiles.

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“…Based on these facts, efforts have been continued to discover new and effective chemotherapeutic agents for the tuberculosis treatment. We recently reported the antitubercular activity of several new molecules with good minimum inhibitory concentrations (MICs), − which promoted us to synthesize new compounds.…”

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confidence: 99%

Synthesis and Antitubercular Activity of New Benzo[b]thiophenes

Mahajan

Nikam

Nawale

et al. 2016

ACS Med. Chem. Lett.

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In vitro and ex vivo efficacies of four series of benzo [b]thiophene-2-carboxylic acid derivatives were studied against Mycobacterium tuberculosis H37Ra (MTB). Benzo [b]thiophenes were also tested in vitro against multidrug resistant Mycobacterium tuberculosis H37Ra (MDR-MTB), and 7b was found to be highly active against A-and D-MDR-MTB/MTB (MIC ranges 2.73−22.86 μg/mL). The activity of all benzo[b]-thiophenes against M. bovis BCG (BCG) was also assessed grown under aerobic and under conditions of oxygen depletion. Compounds 8c and 8g showed significant activity with MICs of 0.60 and 0.61 μg/mL against dormant BCG. The low cytotoxicity and high selectivity index data against human cancer cell lines, HeLa, Panc-1, and THP-1 indicate the potential importance of the development of benzo [b]thiophene-based 1,3-diketones and flavones as lead candidates to treat mycobacterial infections. Molecular docking studies into the active site of DprE1 (Decaprenylphosphoryl-β-D-ribose-2′-epimerase) enzyme revealed a similar binding mode to native ligand in the crystal structure thereby helping to understand the ligand−protein interactions and establish a structural basis for inhibition of MTB. In summary, its good activity in in vitro and ex vivo model, as well as its activity against multidrug-resistant M. tuberculosis H37Ra in a potentially latent state, makes 7b an attractive drug candidate for the therapy of tuberculosis. KEYWORDS: Benzo[b]thiophene, MDR-MTB, M. Bovis BCG, cytotoxicity, molecular dockingA mong infectious widespread diseases, tuberculosis (TB) remains an active and major health problem worldwide. TB is the deadliest communicable disease, caused by the global emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of TB along with acquired, primary, and cross resistance mycobacterium TB (MTB) strains. Despite the availability of first line and second line drugs regimen to treat the disease, still unacceptably TB continues to have high mortality and a global health threat. Resistance to first line anti-TB drugs has been linked to spontaneous mutations in many genes.1 The probability of resistance arising when rifampicin and isoniazid are used in combination is only one in 10 14 , sufficiently low to prevent resistance for either drug.2 As per WHO, the direct observed therapy strategy (DOTS) is the most effective means to prevent the emergence of drug resistance.3 As for those with HIV, several other inter-related factors like poverty, mobility of people from the countries where TB is prevalent, the long and complex TB regimen, and poor management of TB control programs 4 pose the resurgence of TB.Mycobacterium bovis Bacillus Calmette Guerin (BCG), an attenuated strain closely related to MTB, 5 infections in humans have been reported from many centuries ago. M. bovis infections have re-emerged and are causing TB in humans, due to mutations during the long in vitro propagation of this strain and, in particular, those who are HIV-positive. Owing to the appearance of drug resi...

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Design and synthesis of 11α-substituted bile acid derivatives as potential anti-tuberculosis agents

Cited by 20 publications

References 62 publications

Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles

Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles

Molecular perturbations in pulmonary tuberculosis patients identified by pathway-level analysis of plasma metabolic features

Synthesis and Antitubercular Activity of New Benzo[b]thiophenes

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