Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones as a new class of DHFR inhibitors

被引：41
作者：
Al-Rashood, Sarah T. [1 ]
Hassan, Ghada S. [2 ]
El-Messery, Shahenda M. [3 ]
Nagi, Mahmoud N. [4 ]
Habib, El-Sayed E. [5 ]
Al-Omary, Fatmah A. M. [1 ]
El-Subbagh, Hussein I. [2 ]
机构：
[1] King Saud Univ, Coll Pharm, Dept Pharmaceut Chem, Riyadh 11451, Saudi Arabia
[2] Mansoura Univ, Fac Pharm, Dept Med Chem, Mansoura, Egypt
[3] Mansoura Univ, Fac Pharm, Dept Organ Pharmaceut Chem, Mansoura, Egypt
[4] King Saud Univ, Coll Pharm, Dept Pharmacol, Riyadh 11451, Saudi Arabia
[5] Taibah Univ, Coll Pharm, Dept Pharmaceut & Pharmaceut Technol Microbiol, Almadinah Almunawwarah 344, Saudi Arabia
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 18期
关键词：
Synthesis; Quinazolin-4-ones; DHFR inhibition; Antimicrobial testing; Antitumor screening; Molecular modeling study; HUMAN DIHYDROFOLATE-REDUCTASE; NATIONAL-CANCER-INSTITUTE; ANTITUMOR-ACTIVITY; DRUG DISCOVERY; SUBSTITUTED QUINAZOLINES; THYMIDYLATE SYNTHASE; FOLATE ANTAGONISTS; PART; ANALOGS; AGENTS;
D O I：
10.1016/j.bmcl.2014.07.070
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A new series of 2-(1,3,4-thiadiazolyl-or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50 values range of 0.1-0.6 mu M. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4557 / 4567
页数：11
相关论文
共 51 条
[1]   The in vitro antitumor assay of 5-(Z)-arylidene-4-imidazolidinones in screens of AIDS-related leukemia and lymphomas [J].
Al-Madi, S ;
Al-Obaid, AM ;
El-Subbagh, H .
ANTI-CANCER DRUGS, 2001, 12 (10) :835-839
[2]   Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs [J].
Al-Obaid, Abdulrahman M. ;
Abdel-Hamide, Sami G. ;
El-Kashef, Hassan A. ;
Abdel-Aziz, Alaa A. -M. ;
El-Azab, Adel S. ;
Al-Khamees, Hamad A. ;
El-Subbagh, Hussein I. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (06) :2379-2391
[3]  
Al-Omar M. A., 2004, Saudi Pharmaceutical Journal, V12, P63
[4]   Nonclassical antifolates, part 3: Synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones [J].
Al-Omary, Fatmah A. M. ;
Hassan, Ghada S. ;
El-Messery, Shahenda M. ;
Nagi, Mahmoud N. ;
Habib, El-Sayed E. ;
El-Subbagh, Hussein I. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 63 :33-45
[5]   Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones [J].
Al-Omary, Fatmah A. M. ;
Abou-zeid, Laila A. ;
Nagi, Mahmoud N. ;
Habib, El-Sayed E. ;
Abdel-Aziz, Alaa A-M. ;
El-Azab, Adel S. ;
Abdel-Hamide, Sami G. ;
Al-Omar, Mohamed A. ;
Al-Obaid, Abdulrahman M. ;
El-Subbagh, Hussein I. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (08) :2849-2863
[6]   Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs [J].
Al-Rashood, Sarah T. ;
Aboldahab, Ihsan A. ;
Nagi, Mahmoud N. ;
Abouzeid, Laila A. ;
Abdel-Aziz, Alaa A. M. ;
Abdel-hamide, Sarni G. ;
Youssef, Khairia M. ;
Al-Obaid, Abdulrahman M. ;
EI-Subbagh, Hussein I. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (24) :8608-8621
[7]   5-substituted-2-thiohydantoin analogs as a novel class of antitumor agents [J].
AlObaid, AM ;
ElSubbagh, HI ;
Khodair, AI ;
Elmazar, MMA .
ANTI-CANCER DRUGS, 1996, 7 (08) :873-880
[8]  
[Anonymous], 2000, J MED CHEM, DOI DOI 10.1021/jm000038m
[9]  
[Anonymous], 1988, J COMPUT CHEM
[10]  
[Anonymous], SCI PHARM
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