초록 ▼

1) 연구 목적
1. AIDS 치료제로 사용될 수 있는 N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thioure(TET)계 새로운 HIV Non-Nucleoside Reverse Transcriptase Inhibitor 발굴
2. TET의 유효 conformation 연구
2) 연구방법 및 결과
1차년도 연구 결과 요약
1) 유도체 합성 연구연구계획서상의 중간체 intermediates 4-phenylimidazolidinone (20), 4-Phen

1) 연구 목적
1. AIDS 치료제로 사용될 수 있는 N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thioure(TET)계 새로운 HIV Non-Nucleoside Reverse Transcriptase Inhibitor 발굴
2. TET의 유효 conformation 연구
2) 연구방법 및 결과
1차년도 연구 결과 요약
1) 유도체 합성 연구연구계획서상의 중간체 intermediates 4-phenylimidazolidinone (20), 4-Phenylimidazolidinethione(21),4-phenyl1,2,5]thiadiazolidine-1,1-dioxide(22)를 이용한 TET계열 목표 화합물 17종을 합성완료하고 대조약제 2종을 합성함
1. l-phenylalkyl-4-phenylimidazolidin-2-thione 유도체 합성 (중간체 20 유도체)1-benzy1-4-phenylimidazolidin -2- thione (J002)
2. 1-Phenylalkyl-4-phenylimidazolidinone 유도체 합성 (중간체 21 유도체)1-benzyl-4-phenylimidazolidinone (J001), 1-phenylethyl-4-phonylimidazolidinone(J021),1-(2-Oxo -2-phenyl -ethyl)-4-phenyl-imidazolidin-2-one(J022),4-Phony1-1-(3-phenyl-alIyl)-imidazolidin-2-one(J035)
3. (S)-4-phenyl-(1,2,5)thiazolidine-1,1-dioxide 유도체 합성 (중간체 22 유도체)
(R)-4-phenyl-2-benzyl-[1,2,5] thiadiazolidne-1,1-dioxide(J003)
(R)-(-)-4-phenyl-2,5-dibenzyl-[1,2,5]thiadiazolidine-1,1-dioxide(J004)
(S)-4-phenyl-2-benzy1-[1,2,5]thiadiazolidine-1,1-dioxide(J009)
(S)-(-)-4-phenyl-2,5-dibenzyl-[1,2,5]thiadiazolidine-1,1-dioxide (J010)
(S)-(+)-4-phenyl-2-benaoyl-[1,2,5]thiadiazolidine-1,1-dioxide(J005)
(S)-(+)-4-phenyl-5-benzoyl-[1,2,5]thiadiazolidine-1,1-dioxide (J007)
(S)-4-phenyl-2-tolyl-[1,2,5]thiadiazolidine-1,1-dioxide (J006)
(S)-(+)-4-phenyl-5-tolyl-[1,2,5]thiadiazolidine-1,1-dioxide (J008)
(S)-4-phony1-2-phony1carbamoyl-[1,2,5]thidtazolidine-1,1-dioxide(J023)
(S)-4-Phenyl-5-phenylcarbamoyl-[1,2,5]thiadiazolidine-1,1-dioxide(J024)
(S)-(-)-4-phenyl-2-tolylcarbamoyl-[1,2,5]thiadiazolidine-1,1-dioxide(J025)
(S)-4-phenyl-5-toIylcarbamoy1-[1,2,5]thiadiazolidine-1,1-dioxide(J026)
4.대조시약합성
N-(2-(2-Pyridylethyl)-N'-(2-(5-bromopyridyl))thioureaN-(2-(5-bromopyridinyl))
N-(2-(2-thiophenylethyl))thiourea
2) 합성한 TET 유도체의 Anti-HW 효과 측정 완료
합성 유도체중 화합물 J023과 J024의 경우만 약한 항 HRF 효과를 발현함
3) 합성한 유도체와 대조약제 TET와 분자모델 비교분석을 통한 구조찰성관계 연구
2차년도 연구 결과
4). 2-Phenyl(or benzyl)carbamoylaziridine의 합성 및 항바이러스 효과 평가 2-Phenyt(or benzyl)carbamoylaziridine의 유도체의 R과 S form을 선택적으로 합성하였다. 합성 된 유도체는 아래와 같이 총 18종이며, 이들에 대한 항 HIV 활성을 측정한 결과 효과가 없는 것 으로 밝혀졌다.
(S) -2- Phenyl -1- (N-henzylcarbarnoyl ) aziridine (J011)
(S) -2- Phenyl -1- fN- (2- phenylethyl)carbamoyl] aziridine (J0l2)
(S) -2- Phen yl -1- [N- (2- (pyridin-2- yl) ethyl) carbamoyl] i,niriaine (J013)
(S) -2- Phenyl-1- [N- (2- (thiophen-2- yl) ethyl) carbamoyl] aziridine (J014)
(S) -2-Phenyl -1- [N- (3-phenylpropyl) carbamoyl] asiridine (J015)
(R) -2-Phenyl -1- (N-henzylcarbarnoyl) aziridine (J016)
(R) -2- Phenyl -1- [N - (2-phenylethyl) carbamoyl] aziridine (J017)
(R) -2- Phenyl-1- [N - (2- (pyridin-2-yl) ethyl )c arbamoyl]aziridine (J018)
(R) -2- Phenyl -1- [N- (2- (thiophen-2-yl) ethyl )carbamoyl] aziridine (J019)
(R) -2- Phenrl -1- [N - (3- phenyIPropyl ) carbamoy13 aziridine (J02O)
(S) -2- Phenyl -1- [N - (pyridin -2-yl) carbamoyl] aziridine (J027)
(S) -2- Phenyl -1- [N- (5-bromopyridin-2- yl) carbamoyl] aziridine (J028)
(S) -2- Benzyl -1- [N- (pyridin -2yl) c arbamoyl] aziridine (J029)
(S) -2- Benzyl -1- [N - (5- bromopyridin -2- yl) carb amoyl] aziridine (J032)
(R) -2- Phenyl -1- [N - (pyridin-2- yl) carbamoyll aziridine (J03l)
(R) -2- Phenyl -1- [N - (5-bromopyidin -2-yl) c arbamoyl] agiridine (J032)
(R) -2- Benzyl-1- [N- (pyridin -2yl) cwbi,no yll asiridine (J033)
(R) -2- BenByl-1- [N - (5- bro mopyridin-2- yl) carbamoyl] aziridine (J034)
5) aromatic fused analogs, benBirnidazolone 또는 benzimidazolethione유도체의 합성 및 평가 TET conformation을 고정 시킨 유도체를 얻고자 benzirnidaEolone (6종) 또는 benzimidazolethione (5종) 유도체를 설계하고 합성하여 항 HIV 효과를 측정하였다. 이들 화합물들의 conformation은 TET의 유효 conformation과 유사 할 것으로 판단되었다. 그러나 항 바이러 f 효과는 나타나지 않았다.
1- Benzyl -5-methyl -1,3- dihydrobenzoimidazol-2-one (J035)
1- Benzyl -5- methyl -1,3- d ih ydrobenzo imidazo le-2- thione (J041)
5- Methyl -1-phenethyl -1,3- d ihydrob enzo inRid 3n o 1-2- on e ( J036)
5- Mothy 1-1- nhe n ethy 1-1,3- d ihydrob eno imid fn ole -2- thio no (5042)
5- Methyl-1- (3-phenylpropyl ) -1,3- dihydro -benzoimidazol-2- one (J037)
5-M eth y 1-1- (3- phenylpropy 1) -1,3- d ihydro -b euo imid azole -2- thione (J043)
1- Benzyl -5-chloro -1,3-dihydrobenzoimid azol -2-one (J038)
1- Benzy 1-5- c hloro -1,3- di hydroben zoimid azol e -2- thione (J044)
5- Ch toro -1- rhen ethyl -1,3- di, hydrobenz oi mid as of -2- o no (J039)
5-Chloro -1- phenethyl -1,3- dihydrobenzoimid azole-2- thione (J045)
5-Chloro-1- (3- PhenyIPropyl) -1,3- dihydro -benzoimidazol -2-one (J040)

Abstract ▼

1)Purpose of study:
1. Finding the novel IW Non-Nucleoside Reverse Transcriptase Inhibitor based orllN'- [2- (2- thiophene) ethyl] -N'- [ 2- (5-bmmopyiidyl) 3thiourea (TET) for the treatment of AIDS
2. Study of effective conformation of TET
2) Methods and Results:
The first year result

1)Purpose of study:
1. Finding the novel IW Non-Nucleoside Reverse Transcriptase Inhibitor based orllN'- [2- (2- thiophene) ethyl] -N'- [ 2- (5-bmmopyiidyl) 3thiourea (TET) for the treatment of AIDS
2. Study of effective conformation of TET
2) Methods and Results:
The first year results;
1) Synthesis of target structure 1.
From the intermediates 4-phenylimidazolidinone (20), 4-phenyl imidazolidinethione (21) 4-phenyl 1,2,SEthiadiazolidine-1,1-dioxide(E), seveteen compounds and two control agents were prepared
1. Synthesis of 1-phenylalkyl-4-phenylimidazolidin-2-thione (20) derivatives 1-benzyl -4-phenylimidazolidin-2-thione (J002)
2, Synthesis of 1-phenylalkyl-4-phenylimidazolidinone (21) derivatives1-benzyl -4-phenylimidazolidinone (J001), 1-phenylethyl-4-phenylimidazolidlnone(J021), 1- (2-Oxo-2-phenyl-ethyl)-4-phenyl-imidazolidin-2-one(J022), 4-Phenyl-1-(3-phony 1-al1yl)-imidazolidin-2-one(5035)
3. Synthesis of (S)-4-phenyl-[1,2,5]thiazolidine-1,1-dioxide(22)derivatives
(R)-4-pheny -2-benzyl-[1,2,5]thiadiazolidine-1,1-dioxide(J003)
(R)-(-)-4-phenyl-2,5-dibenzyl-[1,2,5]thiadiasolidine-1,1-dioxide(J004)
(S)-4-phony1-2-benzyl-[1,2,5]thiadiazolidine-1,1-dioxide(J009)
(S)-(-)-4-phenyl-2,5-benzyl-[1,2,5]thiadiazolidine-1,1-dioxide(J010)
(S)-(+)-4-phenyl-2-benzoyl-[1,2,5]thiadiaEolidine-1,1-dioxide(J005)
(S)-(+)-4-phenyl-5-benzoyl-[1,2,5]thiadiaEolidine-1,1-dioxide(J007)
(S)-4-phenyl-2-tolyl-[1,2,5]thiadiagolidine-1,1-dioxide(J006)
(S)-(+)-4-phenyl-5-tolyl-[1,2,5]thiadiazolidine-1,1-dioxide(J008)
(S)-4-phenyl-2-phenylcarbamoyl-[1,2,5]thiadinzolidme-1,1-dioxide(J023)
(S)-4-rhenyl-5-phenyIcarbamoy1-[1,2,5]thiadinzolidine-1,1-dioxide(J024)
(S)-(-)-4-pheny1-2-tolylcfubamoy1-[1,2,5]thiadiaEolidine-1,1-dioxide(J025)
(S)-4-pheny1-5-toIylcarbamoyl-[1,2,5]thiadiazolidine-1,1-dioxide (J026)
4,Synthesis of control agents
N-(2-(2-frridylethyl)-N'-(2-(5-bromopyridyl))thiourea
N-(2-(5-bromopyridinyl))-N'-(2-(2-thiophenylethyl))thiourea
2) The Anti-HIV activity of the above compounds prepared as TET analogs were measured. The comrounds 1023 and 1024 showed moderate anti-HIV activity.
3) Structure activity relationship was studied based on the Anti-HIV activity of these analogsIn fcld out the effective conformation of TET.
The second year results:
4). Preparation of 2-phenyl(or benzyl)carbamoylaziridine and their anti-HIV activity Enantimeric preparation of 2-phenyl(or bensyl)carbamoylaziridines was accomplished and these compounds donot show any activity against HIV.
(S)-2-Phenyl-1-(N-henzylcarbarnoyl)aziridine(J01)
(S)-2-Phenyl-1-[N-(2-phenylethyl)carbamoyl]aziridine(J012)
(S)-2-Phenyl-1-[N-(2-(pyridin-2-yl)ethyl)carbamoyl]aziridine(J013)
(S)-2-Phenyl-1-[N-(2-(thiophen-2-yl)ethyl)carbamoyl]aziridine(J014)
(S)-2-Phenyl-1-[N-(3-phenylpropyl)carbamoyl]aziridine(J015)
(R)-2-Phenyl-1-(N-benzylcarbarnoyl)aziridine(J016)
(R)-2-Phenyl-1-[N-(2-phenylethyl)carbamoyl]asiridine(J0l7)
(R)-2-Phenyl-1-[N-(2-(pyridin-2-yl)ethyl)carbamoyl]aziridine(J018)
(R)-2-Phenyl-1-[N-(2-(thiophen-2-yl)ethyl)carbamoyl]aziridine(J019)
(R)-2-Phenyl-1-[N-(3-phenyIpropyl)cubamoyl]aziridine(J02O)
(S)-2-Phenyl-1-[N-(pyridin-2-yl)carbamoyl]aziridine(J027)
(S)-2-Phenyl-1-[N-(5-bromopyridin-2-yl)carbamoyl]aziridine(J028)
(S)-2-Benzyl-1-[N-(puridin-2yl)carbamoyl]asiridine(J029)
(S)-2-Benzyl-1-[N-(5-bromopyridin-2-yl)carbamoy]aziridine(J030)
(R)-2-Phenyl-1-[N-(pyridin-2-yl)carbamoyl]aziridine(J03l)
(R)-2-Phenyl-1-[N-(5-bromopyridin-2-yl)cubamoyl]asiridine(J032)
(R)-2-Benzyl-1-[N-(pyridin-2yl)carbamoyl]aziridine(J033)
(R)-2-BenEyl-1-[N-(5-bromopyridin-2-yl)carbamoyl]aziridine(J034)
5) Preparation of henzirnidazolone or benzimidazolethione analogs as aromatic fused analogs and evaluation of their anti-HIV activity.
Benzimidazolones (six compouns) and benzimidazolethiones (5 compounds) as conformationally regid TET analogs were prepared and tested against HIV. Although the conformations of these compounds are considered to be similar to the effective of TET, these are not active against HIV.
1-Benzyl-5-methyl-1,3-dihydrobenzoimidazol-2-one(J035)
1-Benzyl-5-methyl-1,3-dihydrobenzoimidazole-2-thione(J04l)
5-Methyl-1-phenethyl-1,3-dihydrobenzoimidazol-2-one(J036)
5-Methyl-1-phenethy1-1,3-dihydrobenzoimidazole-2-thione(J042)
5-Methyl-1-(3-phenylpropyl)-1,3-dihydrobenzoimidazol-2-one(J037)
5-Methyl-1-(3-phonyIpropyl)-1,3-dihydrobenzoimidazole-2-thione(J043)
1-Benzyl-5-chloro-1,3-dihydrobenzoimidazol-2-one(J038)
1-Benzyl-5-chloro-1,3-dihydrobenzoimidazole-2-thione(J044)
5-Chloro-1-phenethy1-1,3-dihydrobenzoimidazol-2-one(J039)
5-Chloro-1-phenethy1-1,3-dihydrobenzoimidazole-2-thione(J045)
5-Chloro-1-(3-phenvlnroryl)-1,3-dihydrobenzoimidazole-2-one(J040)

목차 Contents

• 표지 ...1
• 제출문 ...2
• 목차 ...3
• I. 연구개발결과 요약문 ...5
• 연구개발사업 최종보고서 요약문 ...5
• Project Summery ...7
• II. 총괄연구개발과제 연구결과...9
• 1. 총괄연구개발과제의 최종 연구개발 목표...9
• 1) 연구개발의 필요성...9
• 2) 연구개발목적...11
• 3) 연구개발의 목표 및 범위...12
• 4) 연차별 연구개발 추진계획...14
• 2. 총괄연구개발과제의 최종 연구개발 내용 및 결과...15
• 1차년도 연구결과...15
• 1-1. 1-benzyl-4-phenyl-imidazolidin2-one (or thione)의 합성...15
• 1-2. (S)-4-phenyl-[1,2,5]thiadiazolidine-1,1-dioxide 유도체의 합성...16
• 1-3. (S)-4-phenyl-2-arylcarbamoyl-[1,2,5]thiadiazolidine-1,1-dioxide 합성...24
• 1-4. 대조 시약의 합성...25
• 1-5 신규 화합물의 검색...27
• 2차년도 연구결과...29
• 2. 목적구조 1; 2-Phenyl(or benzyl)carbamoylaziridine의 합성...29
• 3. 목적구조 2 (aromatic fused analogs)Benzimidazolone 유도체의 합성...36
• 3. 총괄연구개발과제의 연구결과 고찰 및 결론...56
• (1차년도 연구 결과)...56
• 1) 중간체 20, 21, 22 유도체 합성 연구...56
• 2) 신규 화합물의 검색...59
• 3) 합성한 유도체와 대조약제 TET와 분자모델 비교분석을 통한 구조활성관계 연구...61
• (2차년도 연구 결과)...62
• 1) 분자 설계...62
• 2) 목적구조 1 (2-Phenyl(or benzyl)carbamoylaziridine)의 유도체 연구결과...62
• 3) 목적구조 2 (ammatic fused analogs)의 유도체 연구결과...62
• 4. 총괄연구개발과제의 연구성과 및 목표달성도...72
• 5. 총괄연구개발과제의 활용계획...76
• 6. 첨부서류...76
• 7. 참고문헌...77