서브메뉴
검색
Inhibition of Phosphopantetheinyl Transferase in Mycobacterium tuberculosis and Advances in Stereo- and Regioselective Azepane Synthesis
Inhibition of Phosphopantetheinyl Transferase in Mycobacterium tuberculosis and Advances in Stereo- and Regioselective Azepane Synthesis
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103125
- ISBN
- 9798315712060
- DDC
- 547
- 서명/저자
- Inhibition of Phosphopantetheinyl Transferase in Mycobacterium tuberculosis and Advances in Stereo- and Regioselective Azepane Synthesis
- 발행사항
- [Sl] : The University of North Carolina at Chapel Hill, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 431 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
- 주기사항
- Advisor: Aube, Jeffrey.
- 학위논문주기
- Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
- 초록/해제
- 요약This dissertation focuses on two topics within heterocyclic chemistry: (1) the discovery and library development of thioquinazolinone inhibitors of 4-phosphopantetheinyl transferase in Mycobacterium tuberculosis, and (2) the highly selective preparation of complex azepanes from 4,4ʹ-, 3,3ʹ-, or 2,2ʹ-disubstituted cyclohexanones.A high-throughput screen revealed thioquinazolinone inhibitors of phosphopantetheinyl transferase. Structural additions and modifications to the thioquinazoline scaffold resulted in compounds that were as potent against wild-type Mycobacterium tuberculosis as previously reported phosphopantetheinyl transferase inhibitors. We report the confirmation of their mechanism of action through mutant studies and their narrow spectrum antibiotic activity. Off-target and pharmacokinetic data were improved with this molecular scaffold relative to previous small molecules operating through the same mechanism of action. Metabolic studies revealed that Mycobacterium tuberculosis irreversibly deactivates thioquinazolinones by at least one methylation event depending on compound structure.The systematic exploration of the ring expansion of all-carbon quaternary carbon-bearing cyclohexanones to complex saturated azepanes is also reported below. In this method, under Lewis acidic conditions enantiopure hydroxyalkyl azides react with quaternary carbon-bearing cyclohexanones to selectively yield an iminium ether intermediate that is mildly reduced with NaBH4 into its corresponding aminoalcohol in one pot. We report the two step, one pot transformation of (1) 4,4ʹ-disubstituted cyclohexanones to diastereoselectively yield C4- quaternary azepanes in up to 93% yield and 95:5 dr; (2) enantiopure 3,3ʹ-disubstituted cyclohexanones to regioselectively yield either C3- or C4-quaternary azepanes (based on the configurational matching of starting material and hydroxyalkyl azide) in up to 75% and 95:5 rr; (3) racemic 3,3ʹ-disubstituted cyclohexanones to diastereo- and regioselectively yield both C3- or C4-quaternary azepanes in a parallel kinetic resolution in up to 71% yield and 95:5 dr; and (4) 2,2ʹ-disubstituted cyclohexanones in a highly diastereo-, enantio-, and regioselective kinetic resolution that provides recovered starting material with 35% recovery and 99:1 er and enantiopure C3-quaternary azepane in up to 46% yield and 95:5 rr and dr.
- 일반주제명
- Organic chemistry
- 일반주제명
- Microbiology
- 일반주제명
- Chemistry
- 일반주제명
- Biochemistry
- 키워드
- Cyclohexanones
- 기타저자
- The University of North Carolina at Chapel Hill Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008260126s2025 us c eng d■001000017357063
■00520260202103125
■006m o d
■007cr#unu||||||||
■020 ▼a9798315712060
■035 ▼a(MiAaPQ)AAI31938669
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a547
■1001 ▼aZwerneman, Logan Tyler.
■24510▼aInhibition of Phosphopantetheinyl Transferase in Mycobacterium tuberculosis and Advances in Stereo- and Regioselective Azepane Synthesis
■260 ▼a[Sl]▼bThe University of North Carolina at Chapel Hill▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a431 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-11, Section: B.
■500 ▼aAdvisor: Aube, Jeffrey.
■5021 ▼aThesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
■520 ▼aThis dissertation focuses on two topics within heterocyclic chemistry: (1) the discovery and library development of thioquinazolinone inhibitors of 4-phosphopantetheinyl transferase in Mycobacterium tuberculosis, and (2) the highly selective preparation of complex azepanes from 4,4ʹ-, 3,3ʹ-, or 2,2ʹ-disubstituted cyclohexanones.A high-throughput screen revealed thioquinazolinone inhibitors of phosphopantetheinyl transferase. Structural additions and modifications to the thioquinazoline scaffold resulted in compounds that were as potent against wild-type Mycobacterium tuberculosis as previously reported phosphopantetheinyl transferase inhibitors. We report the confirmation of their mechanism of action through mutant studies and their narrow spectrum antibiotic activity. Off-target and pharmacokinetic data were improved with this molecular scaffold relative to previous small molecules operating through the same mechanism of action. Metabolic studies revealed that Mycobacterium tuberculosis irreversibly deactivates thioquinazolinones by at least one methylation event depending on compound structure.The systematic exploration of the ring expansion of all-carbon quaternary carbon-bearing cyclohexanones to complex saturated azepanes is also reported below. In this method, under Lewis acidic conditions enantiopure hydroxyalkyl azides react with quaternary carbon-bearing cyclohexanones to selectively yield an iminium ether intermediate that is mildly reduced with NaBH4 into its corresponding aminoalcohol in one pot. We report the two step, one pot transformation of (1) 4,4ʹ-disubstituted cyclohexanones to diastereoselectively yield C4- quaternary azepanes in up to 93% yield and 95:5 dr; (2) enantiopure 3,3ʹ-disubstituted cyclohexanones to regioselectively yield either C3- or C4-quaternary azepanes (based on the configurational matching of starting material and hydroxyalkyl azide) in up to 75% and 95:5 rr; (3) racemic 3,3ʹ-disubstituted cyclohexanones to diastereo- and regioselectively yield both C3- or C4-quaternary azepanes in a parallel kinetic resolution in up to 71% yield and 95:5 dr; and (4) 2,2ʹ-disubstituted cyclohexanones in a highly diastereo-, enantio-, and regioselective kinetic resolution that provides recovered starting material with 35% recovery and 99:1 er and enantiopure C3-quaternary azepane in up to 46% yield and 95:5 rr and dr.
■590 ▼aSchool code: 0153.
■650 4▼aOrganic chemistry
■650 4▼aMicrobiology
■650 4▼aChemistry
■650 4▼aBiochemistry
■653 ▼aAntibiotic activity
■653 ▼aMycobacterium tuberculosis
■653 ▼aStructural additions
■653 ▼aCyclohexanones
■690 ▼a0490
■690 ▼a0410
■690 ▼a0487
■690 ▼a0485
■71020▼aThe University of North Carolina at Chapel Hill▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g86-11B.
■790 ▼a0153
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357063▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
