새로운 항균제로서 1-(phenoxymethyl)-benzotriazole유도체의 합성과 정량적인 구조 활성관계(QSAR) 분석

다국어 초록 (Multilingual Abstract)

Thirteen kinds of new 1-(phenoxymethyl)benzotriazoles(3) and 1-(thiophenoxymethyl)benzotriazoles(4) dervatives were synthesized by the reaction of 1-(chloromethyl)benzetriazole and a series of substituted phenols and thiophenols. The reaction products, (3) G (4) derivatives were identified their structure by means of C.H.N. analysis, UV-visible, Infrared, proton magnetic resonance (^1H-NMR) 6 Mass spectroscopy, respectively.
The substituent chemical shifts (SCS) on the methylene group of deuterochloroform and deuteroacetone solution were applied to the Hammett, Taft a Swain-Lupton's simple(SSP) and dual substituent parameter(DSP) equations. From the results of linear free energy relationship (LFER) analysis, the field-effect(F) was larger than resonance-effect(R) in deuterochlo-roform whereas, the resonance-effect(R) was larger than field- effect(F) in deuteroacetone. The results indicate that the resonance-effect(R) could influenced on the chemical shift of methylene group not only through conjugate system of (3) 6 (4) derivatives but also deuteroacetone solvent. And the dissociation constant of 1-(p-nitrophenoxymethyl)benzotriazole(3b) was ca. pKa 6.3 (Ka = 5.0x10^-7).
The antifungal activities of (3) & (4) derivatives were measured in vitro against Pyricularia oryzae (Rice blast), Collectotrichum gloeosporiodes (Anthracnose),Alternaia mali (Alternaria leaf spot), Fusarium oxysporum f. sp. sesami (Fusarium wilt), Trichoderma sp. and so on.
The quantitative structure-activity relationship(QSAR) between obs. ED_50 values against Pyricularia oruzae & Pusarium oxysporum f. sp. sesami and the structure of (3) & (4) derivatives was studied quantitatively by Hansch's multipul parameter method and LFER analysis.
The correlation relationship on the antifungal activity of (3) & (4) derivatives in vitro against Pyricularia oryzae & Fusarium oxysporum f. sp. sesami was consist of two parts, electronic withdrawing group (p>0) and electronic donating group (p<0), respectively. The biphasic electronic relation shows that the antifungal activities of strong electron with- drawing groups, exclusive of 2,4-dinitro group (3a), and strong electronic donating groups were weaker than weak electron donating groups and weak electron withdrawing groups. The substitution effect on the antifungal activities of electron donating groups by C-H hyperconjugation effect (methyl>t-butyl) were larger than electron withdrawing groups. Particularly, antifungal activity of (3e) (p-H) in vitro against Pyricularia oryzae is stronger than commercial agrochemical, Kasugamycin and Oryzaemate, respectively.
Also, antifungal activities of (3) (Y=O) derivatives are stronger than (4) (Y=S) derivatives and the correlation re- gression eguations on the OSAR are repressed as follow;
Pyricuraria oryzae;
ρ>0; ED_50 = -564.574σ-482.230π-515.191Es + 85
ρ>0; ED_50 = -366.979σ-44.327π+5.814Es+85
Fusarium oxysporum f. sp. Sesami;
ρ>0; ED_50 = -1330.436σ-887.552π+1014.085Es+65
ρ>0; ED_50 = -332.137σ-14.138π+45.528Es+65
From the above results, electronic effect, hydrophobic character, steric factor and pKa constant with substituents(X) on the phenoxy or thiophenoxy group influenced significantly on the antifungal activities,
The SSP 6 DSP equations of QSAR and LFER which can be applied to the various substituents of (3) & (4) derivatives suggest that antifungal reaction, the biphasic electronic mechanism by (3) & (4) derivatives in vitro against Pyriculria oryzae and Fusarium oxysporum f. sp. sesami proceed through the SE?reaction involving the formation of carbanium ion by electronic withdrawing group and the reaction proceed through the SE?reaction via transition state by electronic donating group, respectively. On the basis of these findings, we may proposed that the active lead conpounds are (R) or (S) 1-(phenoxy sub. methyl)benzotriazole(I) and 3-methyl-1-(phenoxy sub. methyl)benzotriazolium iodide(II) as new antifungal agents.

목차 (Table of Contents)

• 목차
• I. 서론 = 1
• II. 실험 및 계산 = 4
• 1. 시약 및 기기 = 4
• 2. 1-(hydroxymethyl)benzotriazole(1)의 합성 = 4
• 3. 1-(chloromethyl)benzotriazole(2)의 합성 = 5
• 4. 1-(phenoxymethyl) benzotriazole 유도체 (3a) - (3b)의 합성 = 5
• 5. 1- (thiophenoxymethyl)benzotriazole 유도체 (4a) - (4b)의 합성 = 10
• 6. 1- (azidomethyl)benzotriazole (5)의 합성 = 11
• 7. 단순 (SSP) 및 다중치환 피라미터 (DSP) 식의 계산 = 42
• 8. 항균력 검정과 ED_so값의 측정 = 42
• III. 결과 및 고찰 = 44
• 1. 1.2.3-benzotriazole과 formaldehyde 및 1-(chloromethyl)benzotriazole과 phenol 유도체와의 반응 = 44
• 2. (3)과 (4)유도체의 Electronic spectra와 Mass spectra = 51
• 3. (3)과 (4)유도체중 methylene group의 substituent chemical shift (SCS)에 미치는 자유에너지의 관계 = 59
• 4. 1-(ρ-nitrophenoxymethyl)benzotriazole (3b)의 pKa 상수 = 72
• 5. Ortho nitro group의 여러가지 치환기 상수 계산 = 76
• 6. (3)과 (4) 유도체의 향균작용과 QSAR분석 = 78
• 7. Pyricularia oryzae와 Fusarium oxysporum f. sp. sesami에 대한 향균작용 메카니즘의 가정 = 92
• 8. 새로운 향군제의 분자설계 = 100
• IV. 결론 = 104
• 참고문헌 = 107
• 영문초록 = 114