Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase

Landge, Sudhir; Mullick, Amrita B.; Nagalapur, Kavitha; Neres, João; Subbulakshmi, Venkita; Murugan, K; Ghosh, Anirban; Sadler, C; Fellows, Mick D.; Humnabadkar, Vaishali; Mahadevaswamy, Jyothi; Vachaspati, Prakash; Sharma, Sreevalli; Kaur, Parvinder; Mallya, Meenakshi; Rudrapatna, Suresh; Awasthy, Disha; Sambandamurthy, Vasan K.; Pojer, F.; Cole, Stewart T.; Balganesh, Tanjore S.; Ugarkar, Bheemarao G.; Balasubramanian, V.; Bandodkar, Balachandra; Panda, Manoranjan; Ramachandran, Vasanthi

doi:10.1016/j.bmc.2015.11.017

Cited by 52 publications

(50 citation statements)

References 18 publications

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“…In this context, DprE1 was found to have a very broad specificity for the electron acceptor, being able to use several compounds belonging to very different chemical classes. Indeed, the enzyme can reduce not only quinones, but also indophenols such as 2,6-dichlorophenolindophenol, or the phenoxazine moiety of resazurin, both compounds used in DprE1 activity assays [41,42], as well as different nitroaromatic moieties that characterize several covalent inhibitors of this enzyme [30,32,33,43,44].…”

Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

“…In this way, since the electron acceptor site is occupied, the enzyme is unable to reoxidize the flavin cofactor, resulting in being irreversibly inhibited [41,48] (Figure 1). phenoxazine moiety of resazurin, both compounds used in DprE1 activity assays [41,42], as well as different nitroaromatic moieties that characterize several covalent inhibitors of this enzyme [30,32,33,43,44]. To date, more than 15 chemical classes of compounds inhibiting DprE1 have been reported.…”

Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

“…Currently, 33 DprE1 structures from M. tuberculosis or M. smegmatis have been deposited in the Protein Data Bank, as apoenzyme [41,53] or in complex with both covalent [41,43,44,49,54] and noncovalent inhibitors [43,50,[55][56][57][58]. The enzyme is characterized by the two-domain topology of the vanillyl-alcohol oxidase family of oxidoreductases, which includes a flavin adenine dinucleotide (FAD)-binding domain and the substrate-binding domain [41].…”

Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

“…A series of pyrimidine conjugate of the benzothiazole give a further improvement of this compound, with the best derivatives showing MIC of 0.08-0.09 µM [61]. More recently a new class of inhibiting DprE1 benzothiazoles, benzothiazole-N-oxides, have been identified through a whole cells screening [44], but despite their promising bactericidal activity they showed toxicity issues.…”

Section: Dpre1 Inhibitors Which Are the Current Status And Future Pementioning

confidence: 99%

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Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of high-throughput screenings campaigns, which allowed for the identification of numerous hit compounds and novel targets. Interestingly, several independent screening assays identified the same proteins as the target of different compounds, and for this reason, they were named “promiscuous” targets. These proteins include DprE1, MmpL3, QcrB and Psk13, and are involved in the key pathway for M. tuberculosis survival, thus they should represent an Achilles’ heel which could be exploited for the development of novel effective drugs. Indeed, among the last molecules which entered clinical trials, four inhibit a promiscuous target. Within this review, the two most promising promiscuous targets, the oxidoreductase DprE1 involved in arabinogalactan synthesis and the mycolic acid transporter MmpL3 are discussed, along with the latest advancements in the development of novel inhibitors with anti-tubercular activity.

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Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

Section: Why Dpre1 Is a Promiscuous Targetmentioning

confidence: 99%

Section: Dpre1 Inhibitors Which Are the Current Status And Future Pementioning

confidence: 99%

See 2 more Smart Citations

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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“…DprE1 was characterized as the target of compound ( 34 ). In addition, this compound demonstrated safety profile with low cytotoxicity against human A549 cell line (IC 50 > 100 μM), negative Ames assay and moderate CYP isoform inhibition [60]. …”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

2017

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Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery

Yadav¹,

Soni²,

Tanwar³

et al. 2023

ChemMedChem

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DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in‐depth analysis of the structural requirements for both covalent and non‐covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active‐site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti‐TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein‐binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.

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Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase

Cited by 52 publications

References 18 publications

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery

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