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Synthesis and Structure-Activity Relationships of

Synthesis and Structure-Activity Relationships of 5-Amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]- 8-methylquinolonecarboxylic Acid Antibacterials Having Fluorinated 7-[(3R)-3-(1-Aminocyclopropan-1-yl)pyrrolidin-1-yl] Substituents. Hiroaki Inagaki etc.

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Synthesis and Structure-Activity Relationships of

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  1. Synthesis and Structure-Activity Relationships of 5-Amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]- 8-methylquinolonecarboxylic Acid Antibacterials Having Fluorinated 7-[(3R)-3-(1-Aminocyclopropan-1-yl)pyrrolidin-1-yl] Substituents Hiroaki Inagaki etc. J. Med. Chem. 2003, 46, 1005-1015 분자생명과학부 김미금 2003-06-03

  2. 1. Introduction • Multidrug-resistant Gram-positive pathogens • a. Acqusition of resistance to vancomycin(VRE and vancomycin- • intermediate-resistant staphylococcal strains; VISA), an antibac- • terial agents generally regarded as the agent of last resort • for serious infection • b. Quinolone antibacterial agents의 영역에서는 내성을 가진 Gram- • positive 박테리아에 효능이 있는 약품을 얻기 위한 다양한 시도 및 • travafloxacin(TVFX), moxifloxacin(MFLX), gemifloxacin(GMFX), • gatifloxacin(GFLX) 등의 계발 • c. Driving force for the development of new antibacterial agents • - Antibacterial agents에 대한 Gram-positive bacteria의 내성 • 범위의 증가 • - 임상에서 사용되고 있는 Quinolone이 아닌 몇몇의 물질이 보이는 • 내성 돌연변이와 부작용 2/19

  3. (2) Target molecule a. 선행연구 - C-7 위치에 3-(aminocycleopropal-1-yl)pyrrolidin-1-yl 치환기(R2= c-C3H5)를 포함하는 3-(1-amino-1-substituted-methyl)pyrrolidin-1-yl groups를 갖는 여러 quinolone 유도체의 Gram-positive bacteria에 대한 antibacterial activity - 7-{(3R)-3-(1-amino-1-substituted-methyl)pyrrolidin-1-yl} quinolone 유도체 : 좋은 활성을 보였으나 높은 genotoxicity 가짐 - Genotoxicity를 줄이기 위한 N-1 위치에 cyclopropyl 치환기(R1= H) 대신에 (1R, 2S)-2-fluorocyclopropan-1-yl 치환기((R1= F)의 도입의 유용함 - 5-amino-8-methylquinolone 유도체(R3= NH2)의 Gram-positive bacteria에 대해 antibacterial activity 및 8-methylquinolone 유도체(R3= H)에 비해 적은 chromosomal toxicity의 보고 3/19

  4. b. Target molecule - Genotoxicity를 줄이면서 Gram-positive bacteria에 대해 높은 효능을 보이는 화합물 - C-7 위치에 (3R)-3-(1-aminocyclo-propan-1-yl)pyrrolidin-1-yl 치환기를 갖는 5-amino-1-[(1R,2S)-2-fluorocyclopropan-1-yl]- 8-methylquinolone(1, Figure 1) - 화합물 1 : 높은 antibacterial 활성을 보였지만, micronucleus test에서 양성 반응을 보이고 chromosome injuring test에서 독성 - C-7 pyrrolidine 치환기로의 fluorine atom의 도입의 genotoxicity 감소에 효과를 화합물 1에 도입 4/19

  5. 2. Chemistry (1) Retrosynthesis 5/19

  6. (2) Synthesis of compound 9 ----------------------------------------------- Mechanism(1) 6/19

  7. Mechanism(2) 7/19

  8. (3) Synthesis of compound 17a Reagents: (a) Zn, BrCH2CO2Et, cat. I2/THF, reflux; (b) (1) SOCl2/pyridine, (2) DBU/CH2Cl2 ---------------------------------------------- Mechanism (13 → 14 ; The Reformatsky reaction) 8/19

  9. ---------------------------------------------- Mechanism 9/19

  10. (4) Incorporation of fluorine atom(s) into the pyrrolidinone ring ----------------------------------------------- LDA(Lithium diisopropylamide) : hindered non-nucleophilic strong [(CH3)2CH]2NLi (PhSO2)2NF(N-fluorobenzenesulfonimide) : transfer F+ to enolates and carbanions 10/19

  11. Mechanism (20 → 22 : subsequent Curtius rearrangement reaction) 11/19

  12. (5) Synthesis of compound 27a-d 12/19

  13. (6) Synthesis of final product 1-4 (7) Synthesis of Reference compounds 30, 31 13/19

  14. 3. Results and Discussion (1) 대표적인 Gram-positive와 Gram-negative bacteria에 대한 1-4, 30, 31의 minimum inhibitory concentrations(MICs) (Table 1) -화합물 1-4, 30, 31은 Gram-positive bacteria에 대해 reference quinolones TVFX, MFLX, GFLX, CPFX보다 2-128배 활성 -C-7 위치에 fluorinated pyrrolidine을 갖고있는 화합물 2-4와 non-fluorinated 화합물 1은 거의 동일한 antibacterial 활성 →pyrrolidine substituents에 fluorine atom(s)를 도입하는 것은 antibacterial 활성에 크게 영향을 미치지 않음. 14/19

  15. (2) Result of intravenous single-does toxicity study and micronucleus test (Table 2) a. Intravenous single-does toxicity study - 1 ((3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituent) < 30-31 - 2 (trans-oriented) > 1 (non-fluorinated) = 4 (difluorinated) > 3 (cis-oriented) b. Micronucleus test - Non-fluorinated 화합물 1, 31 : 양성반응 - Fluorinated 화합물 2-4 : 음성반응 15/19

  16. (3) Solubility in water (Table 3) : 3 (fluorinated 화합물) >1 (non-fluorinated 화합물) → fluorine atom이 물에서의 용해도를 향상시키는데 기여 16/19

  17. (4) Antibacterial activities of 3 (DQ- 113) (Table 4) • clinically 분리된 내성을 갖는 Gram-positive bacteria에 대한 MICs가 결정 • 다른 quinoline antibacterial agents, VCM, TEIC, LNZ보다 더 효과적 • levofloxacin-resistant MRSA에 대항하는 QPR/DPR과 비슷한 활성 • PRSP에 대항해서는, 3이 열거된 화합물들 중에서 가장 효능을 보였다. • VRE strains 모두에서 가장 효능을 보였다. 17/19

  18. (5) pharmacokinetic profiles of 3 (DQ- 113)(Table 5) • time-concentration curve에서 높은 plasma concentration과 area • 간, 신장, 폐에서 좋은 분포 경향 18/19

  19. 4. Conclusion (1) C-7 위치에 (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl 치환기를 갖고있는 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones 시리즈 합성 (2) Fluorinated 화합물 2-4는 non-fluorinated 화합물 1과 비교해서 효능을 보였고, Gram-positive bacteria에 대해 reference quinolone보다는 적어도 4배의 효능을 보였다. (3) Fluorinated 화합물들 중에서는 cis-oriented 유도체 3(DQ-113)이 1에 비해서 줄어든 정맥내로의 single-does toxicity를 보였고, 쥐에서 좋은 pharmacokinetic profiles를 보였으며, 시험된 다른 quinolines와 비교했을 때 clinically 분리된 내성을 갖는 Gram-positive bacteria에 대해 더 좋은 antibacterial 활성을 보였다. (4) 화합물 3은 이 논문에서 언급한 것들에 더불어 다른 clinically 분리된 bacteria에 대한 완벽한 antibacterial 활성을 보였고, further preclinical evaluation을 위해 선택되었다. 19/19

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