An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics

Fraser Scott; Ryan Nichol; Abedawn I. Khalaf; Federica Giordani; Kirsten Gillingwater; Soumya Ramu; Alysha Elliott; Johannes Zuegg; Paula Duffy; Michael-Jon Rosslee; Lerato Hlaka; Santosh Kumar; Mumin Ozturk; Frank Brombacher; Michael Barrett; Reto Guler; Colin J. Suckling

doi:10.1016/j.ejmech.2017.05.039

An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics

Fraser Scott, Ryan Nichol, Abedawn I. Khalaf, Federica Giordani, Kirsten Gillingwater, Soumya Ramu, Alysha Elliott, Johannes Zuegg, Paula Duffy, Michael-Jon Rosslee, Lerato Hlaka, Santosh Kumar, Mumin Ozturk, Frank Brombacher, Michael Barrett, Reto Guler, Colin J. Suckling

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Abstract

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MIC80s of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans. MGB-353 and MGB-354 have MIC99s of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.

Original language	English
Pages (from-to)	561-572
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	136
Early online date	17 May 2017
DOIs	https://doi.org/10.1016/j.ejmech.2017.05.039
Publication status	Published - 18 Aug 2017
Externally published	Yes

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Scott, F., Nichol, R., Khalaf, A. I., Giordani, F., Gillingwater, K., Ramu, S., Elliott, A., Zuegg, J., Duffy, P., Rosslee, M-J., Hlaka, L., Kumar, S., Ozturk, M., Brombacher, F., Barrett, M., Guler, R., & Suckling, C. J. (2017). An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics. European Journal of Medicinal Chemistry, 136, 561-572. https://doi.org/10.1016/j.ejmech.2017.05.039

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title = "An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics",

abstract = "This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MIC80s of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans. MGB-353 and MGB-354 have MIC99s of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.",

keywords = "Minor Groove Binders, Anti-infective, Antifungal, Anti-tuberculosis",

author = "Fraser Scott and Ryan Nichol and Khalaf, {Abedawn I.} and Federica Giordani and Kirsten Gillingwater and Soumya Ramu and Alysha Elliott and Johannes Zuegg and Paula Duffy and Michael-Jon Rosslee and Lerato Hlaka and Santosh Kumar and Mumin Ozturk and Frank Brombacher and Michael Barrett and Reto Guler and Suckling, {Colin J.}",

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month = aug,

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doi = "10.1016/j.ejmech.2017.05.039",

language = "English",

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Scott, F, Nichol, R, Khalaf, AI, Giordani, F, Gillingwater, K, Ramu, S, Elliott, A, Zuegg, J, Duffy, P, Rosslee, M-J, Hlaka, L, Kumar, S, Ozturk, M, Brombacher, F, Barrett, M, Guler, R & Suckling, CJ 2017, 'An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics', European Journal of Medicinal Chemistry, vol. 136, pp. 561-572. https://doi.org/10.1016/j.ejmech.2017.05.039

TY - JOUR

T1 - An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics

AU - Scott, Fraser

AU - Nichol, Ryan

AU - Khalaf, Abedawn I.

AU - Giordani, Federica

AU - Gillingwater, Kirsten

AU - Ramu, Soumya

AU - Elliott, Alysha

AU - Zuegg, Johannes

AU - Duffy, Paula

AU - Rosslee, Michael-Jon

AU - Hlaka, Lerato

AU - Kumar, Santosh

AU - Ozturk, Mumin

AU - Brombacher, Frank

AU - Barrett, Michael

AU - Guler, Reto

AU - Suckling, Colin J.

PY - 2017/8/18

Y1 - 2017/8/18

N2 - This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MIC80s of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans. MGB-353 and MGB-354 have MIC99s of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.

AB - This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MIC80s of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans. MGB-353 and MGB-354 have MIC99s of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.

KW - Minor Groove Binders

KW - Anti-infective

KW - Antifungal

KW - Anti-tuberculosis

UR - https://www.journals.elsevier.com/european-journal-of-medicinal-chemistry

U2 - 10.1016/j.ejmech.2017.05.039

DO - 10.1016/j.ejmech.2017.05.039

M3 - Article

VL - 136

SP - 561

EP - 572

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

An Evaluation of Minor Groove Binders as Anti-Fungal and Anti-Mycobacterial Therapeutics

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