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17 pages, 2791 KiB

Open AccessReview

Unveiling DprE1 as a Key Target in the Fight against Tuberculosis: Insights and Perspectives on Developing Novel Antimicrobial Agents

by Maximilien Fil and Sandrine Alibert

BioMed 2024, 4(3), 220-236; https://doi.org/10.3390/biomed4030018 - 25 Jul 2024

Cited by 4 | Viewed by 2619

Abstract

Amid the global health crisis instigated by COVID-19, the resurgence of tuberculosis (TB) has underscored the urgent need for innovative solutions. With TB claiming 1.6 million lives in 2021, it remains a formidable challenge, particularly in underdeveloped regions. Central to Mycobacterium tuberculosis (Mtb) [...] Read more.

Amid the global health crisis instigated by COVID-19, the resurgence of tuberculosis (TB) has underscored the urgent need for innovative solutions. With TB claiming 1.6 million lives in 2021, it remains a formidable challenge, particularly in underdeveloped regions. Central to Mycobacterium tuberculosis (Mtb) pathogenesis is the decaprenylphosphoryl-β-D-ribose oxidase (DprE1)/decaprenylphosphoryl-2-keto-β-D-erythropentose reductase (DprE2) complex, pivotal for synthesizing decaprenylphosphoryl-arabinofuranose (DPA), a critical component of mycobacterial cell walls. DprE1 has emerged as a prime therapeutic target, with several inhibitors in clinical trials. This review elucidates the indispensability of DprE1, examines existing ligands, and delineates key considerations for the development of next-generation anti-TB therapeutics. Our analysis highlights the potential of DprE1 inhibitors to revolutionize TB treatment, emphasizing the need for continued research and development in this area to address the evolving landscape of TB and drug resistance. Full article

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19 pages, 1931 KiB

Open AccessArticle

Synthesis, Activity, Toxicity, and In Silico Studies of New Antimycobacterial N-Alkyl Nitrobenzamides

by João P. Pais, Olha Antoniuk, David Pires, Tiago Delgado, Andreia Fortuna, Paulo J. Costa, Elsa Anes and Luis Constantino

Pharmaceuticals 2024, 17(5), 608; https://doi.org/10.3390/ph17050608 - 9 May 2024

Cited by 1 | Viewed by 1980

Abstract

Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium [...] Read more.

Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 3728 KiB

Open AccessArticle

Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold

by Tiago Delgado, João P. Pais, David Pires, Filipe G. A. Estrada, Rita C. Guedes, Elsa Anes and Luis Constantino

Pharmaceuticals 2024, 17(5), 559; https://doi.org/10.3390/ph17050559 - 27 Apr 2024

Cited by 1 | Viewed by 1697

Abstract

Tuberculosis (TB) continues to be a major global health challenge and a leading cause of death from infectious diseases. Inspired by the results from a previous work by our group on antimycobacterial N-alkylnitrobenzamides, which are structurally related to the nitrobenzamide family of [...] Read more.

Tuberculosis (TB) continues to be a major global health challenge and a leading cause of death from infectious diseases. Inspired by the results from a previous work by our group on antimycobacterial N-alkylnitrobenzamides, which are structurally related to the nitrobenzamide family of decaprenylphosphoryl-β-d-ribose oxidase (DprE1) inhibitors, the present study explored a broad array of substituted benzamides. We particularly focused on previously unexplored 3,5-dinitrobenzamide derivatives. Starting with 3,5-dinitrobenzoic acid, we synthesized a diverse library of amides, incorporating both linear and cyclic amine moieties and also assessed the impact of terminal aromatic groups connected through ether, ester, or amide bonds on the bioactivity of the compounds. The synthesis primarily utilized nucleophilic addition/elimination, S_N2, and Mitsunobu reactions. The activity was impacted mainly by two structural features, the addition of an aromatic moiety as a terminal group and the type of linker. The most interesting compounds (c2, d1, and d2, MIC = 0.031 μg/mL) exhibited activities against Mycobacterium Tuberculosis (Mtb) H37Rv comparable to isoniazid. Complementary computational studies helped elucidate potential interactions with DprE1, enhancing our understanding of the molecular basis of their action. Our findings suggest that the most active compounds provide a promising foundation for the continued development of new antimycobacterial agents. Full article

(This article belongs to the Special Issue Selected Papers from the 9th International Electronic Conference on Medicinal Chemistry (ECMC2023))

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18 pages, 11897 KiB

Open AccessArticle

Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

by Dongguang Fan, Bin Wang, Giovanni Stelitano, Karin Savková, Olga Riabova, Rui Shi, Xiaomei Wu, Laurent R. Chiarelli, Katarína Mikušová, Vadim Makarov, Yu Lu, Yuzhi Hong and Chunhua Qiao

Biomedicines 2023, 11(7), 1975; https://doi.org/10.3390/biomedicines11071975 - 12 Jul 2023

Cited by 3 | Viewed by 2199

Abstract

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2’-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. [...] Read more.

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2’-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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14 pages, 1978 KiB

Open AccessArticle

The Veterinary Anti-Parasitic Selamectin Is a Novel Inhibitor of the Mycobacterium tuberculosis DprE1 Enzyme

by José Manuel Ezquerra-Aznárez, Giulia Degiacomi, Henrich Gašparovič, Giovanni Stelitano, Josè Camilla Sammartino, Jana Korduláková, Paolo Governa, Fabrizio Manetti, Maria Rosalia Pasca, Laurent Roberto Chiarelli and Santiago Ramón-García

Int. J. Mol. Sci. 2022, 23(2), 771; https://doi.org/10.3390/ijms23020771 - 11 Jan 2022

Cited by 16 | Viewed by 3745

Abstract

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis, which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of [...] Read more.

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis, which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of selamectin was determined against a panel of M. tuberculosis mutants. Two strains carrying mutations in DprE1, the decaprenylphosphoryl-β-D-ribose oxidase involved in the synthesis of mycobacterial arabinogalactan, were more susceptible to selamectin. Biochemical assays against the Mycobacterium smegmatis DprE1 protein confirmed this finding, and docking studies predicted a binding site in a loop that included Leu275. Sequence alignment revealed variants in this position among mycobacterial species, with the size and hydrophobicity of the residue correlating with their MIC values; M. smegmatis DprE1 variants carrying these point mutations validated the docking predictions. However, the correlation was not confirmed when M. smegmatis mutant strains were constructed and MIC phenotypic assays performed. Likewise, metabolic labeling of selamectin-treated M. smegmatis and M. tuberculosis cells with ¹⁴C-labeled acetate did not reveal the expected lipid profile associated with DprE1 inhibition. Together, our results confirm the in vitro interactions of selamectin and DprE1 but suggest that selamectin could be a multi-target anti-mycobacterial compound. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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14 pages, 3109 KiB

Open AccessArticle

Molecular Docking Suggests the Targets of Anti-Mycobacterial Natural Products

by Rafael Baptista, Sumana Bhowmick, Jianying Shen and Luis A. J. Mur

Molecules 2021, 26(2), 475; https://doi.org/10.3390/molecules26020475 - 18 Jan 2021

Cited by 27 | Viewed by 5688

Abstract

Tuberculosis (TB) is a major global threat, mostly due to the development of antibiotic-resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents several natural products (NPs) have been shown to have in [...] Read more.

Tuberculosis (TB) is a major global threat, mostly due to the development of antibiotic-resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents several natural products (NPs) have been shown to have in vitro activities against M. tuberculosis. The utility of any NP as a drug lead is augmented when the anti-mycobacterial target(s) is unknown. To suggest these, we used a molecular reverse docking approach to predict the interactions of 53 selected anti-mycobacterial NPs against known “druggable” mycobacterial targets ClpP1P2, DprE1, InhA, KasA, PanK, PknB and Pks13. The docking scores/binding free energies were predicted and calculated using AutoDock Vina along with physicochemical and structural properties of the NPs, using PaDEL descriptors. These were compared to the established inhibitor (control) drugs for each mycobacterial target. The specific interactions of the bisbenzylisoquinoline alkaloids 2-nortiliacorinine, tiliacorine and 13′-bromotiliacorinine against the targets PknB and DprE1 (−11.4, −10.9 and −9.8 kcal·mol⁻¹; −12.7, −10.9 and −10.3 kcal·mol⁻¹, respectively) and the lignan α-cubebin and Pks13 (−11.0 kcal·mol⁻¹) had significantly superior docking scores compared to controls. Our approach can be used to suggest predicted targets for the NP to be validated experimentally, but these in silico steps are likely to facilitate drug optimization. Full article

(This article belongs to the Special Issue Computational Methods in Drug Design and Food Chemistry)

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11 pages, 974 KiB

Open AccessFeature PaperReview

Development of Macozinone for TB treatment: An Update

by Vadim Makarov and Katarína Mikušová

Appl. Sci. 2020, 10(7), 2269; https://doi.org/10.3390/app10072269 - 26 Mar 2020

Cited by 56 | Viewed by 6507

Abstract

Macozinone, a piperazine-benzothiazinone PBTZ169, is currently undergoing Phase 1/2 clinical studies for the treatment of tuberculosis (TB). In this review we summarize the key findings that led to the development of this compound and to identification of its target, decaprenylphospohoryl ribose oxidase DprE1, [...] Read more.

Macozinone, a piperazine-benzothiazinone PBTZ169, is currently undergoing Phase 1/2 clinical studies for the treatment of tuberculosis (TB). In this review we summarize the key findings that led to the development of this compound and to identification of its target, decaprenylphospohoryl ribose oxidase DprE1, which is involved in the synthesis of the essential arabinan polymers of the cell wall in a TB pathogen, Mycobacterium tuberculosis. We present the results of the pilot clinical studies, which raise optimism regarding its further development towards more efficient TB drug regimens. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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19 pages, 4647 KiB

Open AccessFeature PaperReview

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

by Giulia Degiacomi, Juan Manuel Belardinelli, Maria Rosalia Pasca, Edda De Rossi, Giovanna Riccardi and Laurent Roberto Chiarelli

Appl. Sci. 2020, 10(2), 623; https://doi.org/10.3390/app10020623 - 15 Jan 2020

Cited by 53 | Viewed by 6937

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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9 pages, 3284 KiB

Open AccessArticle

Virtual Screening of Small Molecular Inhibitors against DprE1

by Gang Zhang, Song Guo, Huaqing Cui and Jianguo Qi

Molecules 2018, 23(3), 524; https://doi.org/10.3390/molecules23030524 - 27 Feb 2018

Cited by 29 | Viewed by 8661

Abstract

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We [...] Read more.

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package. Two compounds were obtained as hits for inhibiting DprE1 activity in M. tuberculosis and are suitable for further in vitro and in vivo evaluation. Full article

(This article belongs to the Section Medicinal Chemistry)

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17 pages, 775 KiB

Open AccessArticle

Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids

by Lucia Semelková, Petra Janošcová, Carlos Fernandes, Ghada Bouz, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Lucie Navrátilová, Jiří Kuneš, Martin Doležal and Jan Zitko

Molecules 2017, 22(9), 1491; https://doi.org/10.3390/molecules22091491 - 7 Sep 2017

Cited by 13 | Viewed by 7228

Abstract

Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, [...] Read more.

Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL⁻¹ (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL⁻¹. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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