1H-Benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones: Design, synthesis and antitubercular activity

Macchi, Fernanda Souza; Pissinate, Kenia; Villela, Anne Drumond; Abbadi, Bruno Lopes; Rodrigues-Junior, Valnês S.; Nabinger, Débora Dreher; Altenhofen, Stefani; Sperotto, Nathalia Denise de Moura; Dadda, Adílio da Silva; Subtil, Fernanda Teixeira; Freitas, Talita Freitas de; Rauber, Ana Paula Erhart; Borsoi, Ana Flávia; Bonan, Carla Denise; Bizarro, Cristiano Valim; Basso, Luiz Augusto; Santos, Daniel Silas Veras dos; Machado, Pablo

doi:10.1016/j.ejmech.2018.06.005

Cited by 27 publications

(15 citation statements)

References 19 publications

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“…These small heterocyclic moieties are incorporated in structural framework of different anti-proliferative, [10] anti-inflammatory, [11,12] anticancer, [13,14] antimicrobial, [15] anti-tubercular agents. [16,17] Many nitrogen atom containing azolic templates have recently been reported as antiurease agents as well. Norfloxacin hybrids, [18] conazole analogue, [19] benzimidazole derivatives, [20] thiazole derivative, [21] azol-β-lactam, [22] benzisoelenazolone, [23] urea-triazole conjugate, [24] thiadiazole derivative [25] are some of the crucial examples ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Azoles possessed distinct structural importance due to their capability of making hydrogen bonds and other non‐covalent interactions with target sites of various enzymes. These small heterocyclic moieties are incorporated in structural framework of different anti‐proliferative, anti‐inflammatory, anticancer, antimicrobial, anti‐tubercular agents . Many nitrogen atom containing azolic templates have recently been reported as antiurease agents as well.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Imidazolylpyrazole Ligands as Potent Urease Inhibitors: Synthesis, Antiurease Activity and In Silico Docking Studies

et al. 2020

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Towards discovery of effective urease inhibitors; we disclose here a hybrid series of imidazole and pyrazole motifs as potent antiurease agents. A para-toluenesulfonic acid (TsOH) catalyzed, facile synthetic approach was employed for the preparation of targeted molecular designs in good yields upto 94 %. The novel scaffolds were characterized by different spectroscopic means (FTIR, NMR, and Mass spectrometry) and elemental analysis helped to identify the purity of these compounds. Afterwards, the derivatives was tested against Jack bean's urease enzyme to explore their inhibiting potencies. All analogues (4 a-4 l) were found active against the studied enzyme in comparison with the standard drug thiourea (IC 50 = 21.26 � 0.12 μM). However, following dibromo substituted derivatives: 4 f, 4 g, 4 h, 4 i, 4 j, 4 k, and 4 l were surfaced out as potent urease inhibitors among the series. The identified lead candidates were meta-nitro substituted 4 k with IC 50 = 0.7 � 0.002 μM and a para-nitro containing compound 4 l with IC 50 = 1.0 � 0.003 μM. As observed in docking calculations, ionic and hydrogen bonding, π-stacking, interaction with nickel ions and other hydrophobic interactions probably stabilized the ligand bindings at the active site of urease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Imidazolylpyrazole Ligands as Potent Urease Inhibitors: Synthesis, Antiurease Activity and In Silico Docking Studies

et al. 2020

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“…Compounds based on the benzimidazole core are being actively studied by different research groups as antimycobacterial agents, especially against tuberculosis 156‐158 . Two compounds of this chemical class, SPR719 and EJMCh‐6, have been found to effectively inhibit the M. abscessus complex.…”

Section: Promising Small‐molecule Inhibitors Of M Abscessus: Light At the End Of The Tunnel?mentioning

confidence: 99%

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

Egorova¹,

Jackson

Gavrilyuk³

et al. 2021

Medicinal Research Reviews

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The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti‐M. abscessus small‐molecule drug development process can be enhanced by two parallel strategies—discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small‐molecule agents, and more particularly focuses on the activity, mode of action and structure–activity relationship of promising inhibitors from five different chemical classes—benzimidazoles, indole‐2‐carboxamides, benzothiazoles, 4‐piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development.

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“…Despite the capacity of these new pharmacological alternatives to treat TB, the high capability for adaptation and the development of mutations associated with resistance [ 7 ] have highlighted the importance of continuous efforts to discover and develop new anti-TB drugs. Our research group has synthesized and evaluated different heterocyclic compounds against drug-susceptible and drug-resistant Mtb strains, with some encouraging results [ 8 , 9 , 10 ]. Importantly, the indole scaffold has been described in compounds endowed with antitubercular activity [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimycobacterial Activity of 3-Phenyl-1H-indoles

et al. 2021

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Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.

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1H-Benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones: Design, synthesis and antitubercular activity

Cited by 27 publications

References 19 publications

Identification of Imidazolylpyrazole Ligands as Potent Urease Inhibitors: Synthesis, Antiurease Activity and In Silico Docking Studies

Identification of Imidazolylpyrazole Ligands as Potent Urease Inhibitors: Synthesis, Antiurease Activity and In Silico Docking Studies

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

Synthesis and Antimycobacterial Activity of 3-Phenyl-1H-indoles

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