Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition

Aroso, Rafael T.; Guedes, Rita C.; Pereira, Mariette M.

doi:10.3390/molecules26051326

Cited by 6 publications

(2 citation statements)

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“…Other 2-substituted benzimidazole derivatives have also shown activity as analgesics, anti-inflammatory [30] and antibacterial agents [31]. Furthermore, docking studies showed that 2, 5 (6) substituted benzimidazole derivatives are also molecules with potential as antimicrobial agents [32]. The importance of the substituents in position 2 and 5 in benzimidazole had been also reported [33].…”

Section: Discussionmentioning

confidence: 93%

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Betancourt-Conde

Avitia-Domínguez

Hernández‐Campos

et al. 2021

IJMS

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Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.

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Section: Discussionmentioning

confidence: 93%

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Betancourt-Conde

Avitia-Domínguez

Hernández‐Campos

et al. 2021

IJMS

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“…Recently, Aroso and co-workers computationally designed benzimidazole derivatives through palladium-catalyzed reactions [69]. The reaction between 4-bromo-1,2-diaminobenzene and 2-nitrobenzaldehyde, followed by a couple of palladiumcatalyzed Suzuki-Miyaura and Buchwald-Hartwig amination cross-coupling reactions resulted in the formation of ( 68) and ( 69)(Figure 17).…”

Section: Antibacterial and Antifungal Activitymentioning

confidence: 99%

Exploring the Versatility of Benzimidazole Scaffolds as Medicinal Agents: A Brief Update

Kavya¹,

Sivan²

2022

Benzimidazole

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Benzimidazole, one of the finest classes of heterocyclic aromatic compounds have the characteristic structure of benzene fused with a five-membered imidazole ring. Despite being made their first appearance in the late 1870s, they are considered as a ‘privileged molecule’. The applications of this wonder molecule range from medicinal chemistry to material science. Benzimidazole being a potent inhibitor for various enzymes has got therapeutic effects like anticancer, antimicrobial, anthelmintic, antioxidant, anticonvulsant, antifungal, anti-inflammatory, antiviral, antihistaminic, antipsychotic, etc. It has also made its existence in various branches of medical science viz ophthalmology, neurology, cardiology and more. The applications of benzimidazole are not only limited to the biological field but also expanded to the field of material chemistry as well. This chapter summarizes the pharmacological properties of benzimidazole, illustrated on numerous derivatives since 2016.

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Design, Synthesis and Biological Evaluation of C3‐Indolyl/(3‐chloro‐indolyl)‐C4‐aryl/heteroaryl‐azetidin‐2‐ones

Yadav,

Fatimah,

Sahoo

et al. 2024

ChemMedChem

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Herein, trans‐ and cis‐azetidin‐2‐ones 3‐6 were strategically synthesized, capitalizing on the bioactivity of azetidin‐2‐ones and indole pharmacophore, followed by a comprehensive characterization using a diverse array of spectroscopic techniques. The sixteen azetidin‐2‐ones were examined for antimicrobial activities against both Gram‐negative (P. aeruginosa, E. coli, A. baumannii) and Gram‐positive bacteria (S. aureus, E. faecium, B. cereus), as well as against C. albicans and C. tropicalis fungal strains. The highly potent compounds (5a, 6b, 6d) demonstrated maximum inhibition against all multidrug‐resistant strains, with minimum inhibitory concentrations ranging from 0.97‐3.9 μg/mL, surpassing the potency of standard ampicillin (MIC: 3.12‐50 μg/mL). Moreover, 6b and 6d exhibited significant inhibitory effects on C. albicans (MIC: 0.97 μg/mL), comparable to fluconazole. The presence of C3‐(3‐chloro‐indolyl) scaffold, combined with diverse electronic effects at N1/C4‐centers, particularly the inclusion of thiophen‐2‐yl motif, greatly influenced the activity of target compounds. Assessment of 4d, 4i‐k and 6d on THLE‐2 cell lines revealed their preferential safety. Molecular docking studies revealed seven compounds with active dual targeting of DNA GyrB and PBP2a proteins, demonstrating a potent broad‐spectrum antibacterial effect. In silico ADME analysis affirms positive drug‐likeness and favorable pharmacokinetic characteristics of indole‐derived hybrids, indicating a promising potential for addressing challenges in evolving multidrug resistance.

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Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition

Cited by 6 publications

References 50 publications

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Exploring the Versatility of Benzimidazole Scaffolds as Medicinal Agents: A Brief Update

Design, Synthesis and Biological Evaluation of C3‐Indolyl/(3‐chloro‐indolyl)‐C4‐aryl/heteroaryl‐azetidin‐2‐ones

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