Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis

Renuka, Janupally; Reddy, K. Indrasena; Konduri, Srihari; Jeankumar, Variam Ullas; Morla, Shravan; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Babu, K. Sudhakar; Sriram, Dharmarajan

doi:10.1016/j.bmc.2014.06.041

Cited by 52 publications

(29 citation statements)

References 19 publications

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“…Numerous examples of Cu (II) and Zn (II) complexes have been explored for their significant antimicrobial activity [20]. Based on these facts, supported by literature [21] Figure 1 and in continuation of our current research interest in the field of synthesis and antimicrobial study of heterocyclic compounds [22][23][24][25][26], we have synthesized and screened the antimicrobial activity of series of transition metal complexes of new Schiff base ligands derived from ethyl 5-aminobenzofuran-2carboxylate.…”

Section: Introductionmentioning

confidence: 86%

Synthesis, characterization and antibacterial activity of Cu (II) and Zn (II) complexes of 5-aminobenzofuran-2-carboxylate Schiff base ligands

Nazirkar

Mandewale

Yamgar³

2019

Journal of Taibah University for Science

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The ever-increasing spread of bacterial infection with rising antibacterial drug resistance has become a matter of global concern in the modern times. Therefore, such serious infections leading to high mortality rate has necessitated the search for new classes of effective antibacterial agents with minimum toxicity. Herein, we report the synthesis and identification of a new class of benzofuran based Schiff ligands (6a-6e) and their Cu/Zn complexes (7a-7j) via sequential reactions starting with Salicylaldehyde. Compounds 6a, 7c and 7e exhibit activity in the low microgram range against M. tuberculosis, showing the minimum inhibitory concentrations (MICs) of 1.6 µg/mL. The compounds 6e and 7b also show interesting antibacterial activity against S. Aureus, E. coli and B. Subtilis with comparable area of inhibition of standard drugs under study. This research suggests that benzofuran based compounds can serve as a promising lead scaffold in developing new drugs to combat microbial infections.

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Section: Introductionmentioning

confidence: 86%

Synthesis, characterization and antibacterial activity of Cu (II) and Zn (II) complexes of 5-aminobenzofuran-2-carboxylate Schiff base ligands

Nazirkar

Mandewale

Yamgar³

2019

Journal of Taibah University for Science

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“…Além disso, a atividade biológica de diversos heterociclicos já foram descritos como sendo ativos contra a subunidade GyrB, como por exemplo derivados de cumarina, benzimidazol uréia, pirazol, indazol e indolinona. 110,111 Utilizando inibidores de GyrB identificados previamente, foram sintetizados 26 derivados do etil 5-(piperazina-1-il) benzofurano-2--carboxilato, que foram avaliados contra cepas de MTB H 37 Rv. O composto 41 se apresentou como o mais promissor da série, exibindo uma CIM 90 de 9.18 μmol L -1 .…”

Section: Dna Girase E Topoisomerase Iunclassified

“…Além disso, o composto 41 foi capaz de inibir a enzima DNA girase B (GyrB) no Mycobacterium smegmatis com IC 50 de 3,2 μmol L -1 (Figura 15). 110 Em outro estudo, foram identificados derivados de benzimidazol uréias em uma biblioteca da empresa farmacêutica AstraZeneca como potenciais inibidores da enzima GyrB contra M. smegmatis. O composto 42 (Figura 15) exibiu CIM 90 igual a 0,5 μmol L -1 contra MTB H 37 Rv e valor de IC 50 igual a 0,5 nmol L -1 na inibição da enzima GyrB.…”

Section: Dna Girase E Topoisomerase Iunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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“…[3] Bacterial DNA gyrase Bi savalidated drug target involved in bacterial DNA synthesis. [4][5][6][7][8][9] Ta rgeting this enzymeb yu sing fragment-based screening has been reported. [10][11][12][13][14][15] Most of the early fragment screens were focusedo nu sing nuclear magnetic resonance (NMR) spectroscopy techniques to identify fragments.…”

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confidence: 99%

Application of Fragment‐Based Drug Discovery against DNA Gyrase B

Chen

Tan

et al. 2015

ChemPlusChem

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Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well‐validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1,800 compounds identified 14 fragments that bind to Escherichia coli (E. coli) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X‐ray crystallography, modifications on a low‐affinity fragment (KD=253 μM, IC50=634 μM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50=160 nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X‐ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

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Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis

Cited by 52 publications

References 19 publications

Synthesis, characterization and antibacterial activity of Cu (II) and Zn (II) complexes of 5-aminobenzofuran-2-carboxylate Schiff base ligands

Synthesis, characterization and antibacterial activity of Cu (II) and Zn (II) complexes of 5-aminobenzofuran-2-carboxylate Schiff base ligands

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Application of Fragment‐Based Drug Discovery against DNA Gyrase B

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