1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX,COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India;2. Immunochemistry Lab, Natural Product Division, ACSIR-IICT-Hyderabad, India;3. Department of Chemistry, School of Chemical and Lifescience, Jamia Hamdard, New Delhi, India;4. SVAK Life Sciences, Pragati Nagar, Hyderabad 500090, India;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, 21311, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;4. Pharmacology Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt;5. Department of Veterinary Medicine, Faculty of Agricultural and Veterinary Medicine, Qassim University, P.O. Box 1482, Buraydah, Al-Qassim, Saudi Arabia;6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University in Alexandria, 21311, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Faculty of Pharmacy, Omar-Almukhtar University, Libya;3. Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt;1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia;4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;5. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;6. Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia;7. Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt;8. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia;9. Histology Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt;10. School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen, AB243UE, Ireland;1. Laboratório de Farmacologia e Inflamação (LABFAR), FACFAN - Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal do Mato Grosso do Sul, UFMS, Campo Grande, MS, Brazil;2. Laboratório de Síntese e Química Medicinal (LASQUIM), FACFAN - Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal do Mato Grosso do Sul, UFMS, Campo Grande, MS, Brazil;3. Departamento de Análises Clínicas e Toxicológicas da Universidade Federal de Minas Gerais, UFMG, Belo Horizonte, MG, Brazil;1. Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India;2. School of Life Sciences, University of Hyderabad, Hyderabad, India |
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| Abstract: | To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC50 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC50 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC50 values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC50 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69–77% inhibition at 3 h, 75–82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX. |
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| Keywords: | Indole-3-glyoxamide derivatives 1,2,3-triazoles COX-1 COX-2 5-LOX Tubulin Anti-proliferation |
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