Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

Oluseye K. Onajole; Shichun Lun; Young Ju Yun; Damkam Y. Langue; Michelle Jaskula-Dybka; Adrian Flores; Eriel Frazier; Ashle C. Scurry; Ambernice Zavala; Karen R. Arreola; Bryce Pierzchalski; A. Jean Luc Ayitou; William R. Bishai

doi:10.1111/cbdd.13739

Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

Oluseye K. Onajole, Shichun Lun, Young Ju Yun, Damkam Y. Langue, Michelle Jaskula-Dybka, Adrian Flores, Eriel Frazier, Ashle C. Scurry, Ambernice Zavala, Karen R. Arreola, Bryce Pierzchalski, A. Jean Luc Ayitou, William R. Bishai

School of Medicine

Research output: Contribution to journal › Letter › peer-review

1 Scopus citations

Abstract

Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.

Original language	English (US)
Pages (from-to)	1362-1371
Number of pages	10
Journal	Chemical Biology and Drug Design
Volume	96
Issue number	6
DOIs	https://doi.org/10.1111/cbdd.13739
State	Published - Dec 2020

Keywords

Imidazo[1,2-apyridine-3-carboxamide
Indole-2-carboxamide
antituberculosis activity

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Organic Chemistry

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10.1111/cbdd.13739

Cite this

Onajole, O. K., Lun, S., Yun, Y. J., Langue, D. Y., Jaskula-Dybka, M., Flores, A., Frazier, E., Scurry, A. C., Zavala, A., Arreola, K. R., Pierzchalski, B., Ayitou, A. J. L., & Bishai, W. R. (2020). Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents. Chemical Biology and Drug Design, 96(6), 1362-1371. https://doi.org/10.1111/cbdd.13739

Onajole, OK, Lun, S, Yun, YJ, Langue, DY, Jaskula-Dybka, M, Flores, A, Frazier, E, Scurry, AC, Zavala, A, Arreola, KR, Pierzchalski, B, Ayitou, AJL & Bishai, WR 2020, 'Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents', Chemical Biology and Drug Design, vol. 96, no. 6, pp. 1362-1371. https://doi.org/10.1111/cbdd.13739

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abstract = "Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.",

keywords = "Imidazo[1,2-apyridine-3-carboxamide, Indole-2-carboxamide, antituberculosis activity",

author = "Onajole, {Oluseye K.} and Shichun Lun and Yun, {Young Ju} and Langue, {Damkam Y.} and Michelle Jaskula-Dybka and Adrian Flores and Eriel Frazier and Scurry, {Ashle C.} and Ambernice Zavala and Arreola, {Karen R.} and Bryce Pierzchalski and Ayitou, {A. Jean Luc} and Bishai, {William R.}",

note = "Funding Information: O.K.O. acknowledge financial support for this project from Roosevelt University Faculty Startup fund and the 2019 Roosevelt University Summer Grant. O.K.O. and A.F. acknowledge the Roosevelt University Ronald E. McNair Post‐Baccalaureate Achievement Program for its generous financial support. This material is also based upon work supported by the National Science Foundation under a CAREER grant no. 1753012 awarded to A.J.A. NIH funding grants AI37856 and HL133190 to W.R.B. Publisher Copyright: {\textcopyright} 2020 John Wiley & Sons A/S",

year = "2020",

month = dec,

doi = "10.1111/cbdd.13739",

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T1 - Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

AU - Onajole, Oluseye K.

AU - Lun, Shichun

AU - Yun, Young Ju

AU - Langue, Damkam Y.

AU - Jaskula-Dybka, Michelle

AU - Flores, Adrian

AU - Frazier, Eriel

AU - Scurry, Ashle C.

AU - Zavala, Ambernice

AU - Arreola, Karen R.

AU - Pierzchalski, Bryce

AU - Ayitou, A. Jean Luc

AU - Bishai, William R.

N1 - Funding Information: O.K.O. acknowledge financial support for this project from Roosevelt University Faculty Startup fund and the 2019 Roosevelt University Summer Grant. O.K.O. and A.F. acknowledge the Roosevelt University Ronald E. McNair Post‐Baccalaureate Achievement Program for its generous financial support. This material is also based upon work supported by the National Science Foundation under a CAREER grant no. 1753012 awarded to A.J.A. NIH funding grants AI37856 and HL133190 to W.R.B. Publisher Copyright: © 2020 John Wiley & Sons A/S

PY - 2020/12

Y1 - 2020/12

N2 - Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.

AB - Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.

KW - Imidazo[1,2-apyridine-3-carboxamide

KW - Indole-2-carboxamide

KW - antituberculosis activity

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DO - 10.1111/cbdd.13739

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SN - 1747-0277

VL - 96

SP - 1362

EP - 1371

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

IS - 6

ER -

Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

Abstract

Keywords

ASJC Scopus subject areas

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