Synthesis,biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, P.O. Box 11562, Cairo, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt;4. Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt;5. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt;6. Department of Microbiology, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt;1. Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt;2. Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt;3. Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt;4. Institute of Analytical Chemistry, Chemo and Biosensors, Universitätsstrasse 31, 93053 Regensburg, Germany;1. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India;2. Faculty of Life Sciences and Biology, South Asian University, New Delhi 110021, India;3. Faculty of Pharmacy, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia;4. Faculty of Applied Science, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia;5. Faculty of Medical Sciences, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia;6. Department of Chemistry, School of Chemical and Life Science, Jamia Hamdard, New Delhi, India;1. Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;2. Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;1. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, AlKharj, Saudi Arabia;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;4. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;5. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt;1. Applied Science Faculty, Samarra University, Iraq;2. EMAN Biodiscoveries Sdn. Bhd., A1-4, Lot 5, Persiaran 2/1, Kedah Halal Park, Kawasan Perindustrian Sungai Petani, 08000, Sungai Petani, Kedah, Malaysia;3. School of Chemical Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia;4. School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia;5. ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National Universityand Eman Research Ltd, Acton, Australia |
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| Abstract: | A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01 μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5 μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively. |
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| Keywords: | Synthesis Quinazolin-4-ones DHFR inhibition Antimicrobial activity Antitumor screening molecular modeling study |
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