Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

被引：24

作者：

Cotman, Andrej Emanuel ^{[1
]}

Durcik, Martina ^{[1
]}

Tiz, Davide Benedetto ^{[1
,2
]}

Fulgheri, Federica ^{[1
,3
]}

Secci, Daniela ^{[1
,3
]}

Sterle, Masa ^{[1
]}

Mozina, Stefan ^{[1
,4
]}

Skok, Ziga ^{[1
,4
]}

Zidar, Nace ^{[1
]}

Zega, Anamarija ^{[1
]}

Ilas, Janez ^{[1
]}

Masic, Lucija Peterlin ^{[1
]}

Tomasic, Tihomir ^{[1
]}

Hughes, Diarmaid ^{[5
]}

Huseby, Douglas L. ^{[5
]}

Cao, Sha ^{[5
]}

Garoff, Linnea ^{[5
]}

Fernandez, Talia Berruga ^{[5
]}

Giachou, Paraskevi ^{[5
]}

Crone, Lisa ^{[5
]}

Simoff, Ivailo ^{[6
]}

Svensson, Richard ^{[6
]}

Birnir, Bryndis ^{[7
]}

Korol, Sergiy V. ^{[7
]}

Jin, Zhe ^{[7
]}

Vicente, Francisca ^{[8
]}

Ramos, Maria C. ^{[8
]}

de la Cruz, Mercedes ^{[8
]}

Glinghammar, Bjorn ^{[9
]}

Lenhammar, Lena ^{[11
]}

Henderson, Sara R. ^{[10
,12
]}

Mundy, Julia E. A. ^{[10
]}

Maxwell, Anthony ^{[10
]}

Stevenson, Clare E. M. ^{[10
]}

Lawson, David M. ^{[10
]}

Janssen, Guido V.

Sterk, Geert Jan

Kikelj, Danijel ^{[1
]}

机构：

[1] Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia

[2] Univ Perugia, Dept Pharmaceut Sci, Via Liceo 1, I-06100 Perugia, Italy

[3] Univ Cagliari, Dept Life & Environm Sci, Drug Sect, Via Osped 72, I-09124 Cagliari, Italy

[4] Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia

[5] Uppsala Univ, Dept Med Biochem & Microbiol, S-75123 Uppsala, Sweden

[6] Uppsala Univ, Dept Pharm, Drug Optimizat & Pharmaceut Profiling Platform UDO, S-75123 Uppsala, Sweden

[7] Uppsala Univ, Dept Med Cell Biol, S-75123 Uppsala, Sweden

[8] Fundac MEDINA, Granada 18016, Spain

[9] RISE Res Inst Sweden, Dept Chem Proc & Pharmaceut Dev, Unit Chem & Pharmaceut Safety, S-15136 Sodertalje, Sweden

[10] John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England

[11] Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden

[12] Univ Birmingham, Inst Microbiol & Infect, Coll Med & Dent Sci, Birmingham, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 02期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

DRUG DISCOVERY; ANTAGONISTS;

D O I：

10.1021/acs.jmedchem.2c01597

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

引用

页码：1380 / 1425

页数：46

共 59 条

[1] Mechanism of Quinolone Action and Resistance
Aldred, Katie J.
Kerns, Robert J.
Osheroff, Neil
[J]. BIOCHEMISTRY, 2014, 53 (10) : 1565 - 1574
[2] [Anonymous], OECD: Test Guideline 428: Skin Absorption in vitro method
[3] [Anonymous], PRIORITIZATION PATHO
[4] [Anonymous], COLORIMETRIC MTS ASS
[5] Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics
Ballard, Peter
Bradbury, Robert H.
Harris, Craig S.
Hennequin, Laurent F. A.
Hickinson, Mark
Kettle, Jason G.
Kendrew, Jane
Klinowska, Teresa
Ogilvie, Donald J.
Pearson, Stuart E.
Williams, Emma J.
Wilson, Ingrid
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (18) : 4908 - 4912
[6] Recent progress in the discovery and development of DNA gyrase B inhibitors
Barancokova, Michaela
Kikelj, Danijel
Ilas, Janez
[J]. FUTURE MEDICINAL CHEMISTRY, 2018, 10 (10) : 1207 - 1227
[7] A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV
Bisacchi, Gregory S.
Manchester, John I.
[J]. ACS INFECTIOUS DISEASES, 2015, 1 (01): : 4 - 41
[8] Breeze A. L., 2005, Patent No. 2005026149
[9] Synthesis of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]-quinoline-1,4,10(5H)-triones as NMDA glycine-site antagonists
Brown, DG
Urbanek, RA
Bare, TM
McLaren, FM
Horchler, CL
Murphy, M
Steelman, GB
Empfield, JR
Forst, JM
Herzog, KJ
Xiao, WH
Dyroff, MC
Lee, CMC
Trivedi, S
Neilson, KL
Keith, RA
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (20) : 3553 - 3556
[10] Improvement of molecular-replacement models with Sculptor
Bunkoczi, Gabor
Read, Randy J.
[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2011, 67 : 303 - 312

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