Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach
Authors
Nedeljković, NikolaDobričić, Vladimir
Bošković, Jelena
Vesović, Marina
Bradić, Jovana
Anđić, Marijana
Kočović, Aleksandar
Jeremić, Nevena
Novaković, Jovana
Jakovljević, Vladimir
Vujić, Zorica
Nikolić, Miloš
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The aim of the conducted study was to develop new potential dual COX-2 and 5-LOX
inhibitors based on naproxen scaffold. We performed the evaluation of in vivo and in vitro
anti-inflammatory activity of newly synthesized thiourea derivatives of naproxen containing
m-anisidine and N-methyl tryptophan methyl ester in a side chain. An in vivo study
was carried out using a carrageenan-induced paw edema model of acute inflammation.
COX-2 and 5-LOX inhibitory potential of synthesized compounds was evaluated using
fluorometric inhibitor screening kits. In silico study was performed in OEDocking 3.2.0.2
software with the FRED tool. Two investigated derivatives exhibited comparable anti-inflammatory
activity to naproxen (56.32%) four hours after injection of carrageenan, with
the percentage of inhibition being 54.01% (m-anisidine derivative) and 54.12% (N-methyl
tryptophan methyl ester derivative). In vitro studies of COX-2 inhibition demonstrated that
none of the tested compounds ach...ieved 50% inhibition at concentrations below 100 μM,
whereas the m-anisidine derivative accomplished comparable inhibition of 5-LOX (IC50 =
0.30 μM) to commercial 5-LOX inhibitor zileuton (IC50 = 0.36 μM). Inability of the tested
compounds to form three hydrogen bonds with ARG120 and TYR355 could be a reason
why these compounds showed weak COX-2 inhibition. The m-anisidine derivative formed
a more stable complex with the 5-LOX enzyme (−8.39 kcal/mol), compared to N-methyl
tryptophan methyl ester derivative (−7.98 kcal/mol), with the absence of the iron ion chelation
in the active site in both cases. The significant in vivo anti-inflammatory activity of
the m-anisidine derivative, together with the potent inhibition of 5-LOX, highlighted this
compound as a promising anti-inflammatory agent.
Keywords:
naproxen / thiourea / anti-inflammatory activity / COX-2 and 5-LOX / FREDSource:
9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia, 2023Publisher:
- Fakultet medicinskih nauka Univerziteta u Kragujevcu
Funding / projects:
- InfCanPlay - Utilization of interplay between inflammation and cancer in the development of compounds with anticancer activity (RS-ScienceFundRS-Ideje-7739840)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200111 (University of Kragujevac, Faculty of Medicine) (RS-MESTD-inst-2020-200111)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200161 (University of Belgrade, Faculty of Pharmacy) (RS-MESTD-inst-2020-200161)
- Faculty of Medical Sciences, University of Kragujevac (Junior Project 11/20)
Institution/Community
PharmacyTY - CONF AU - Nedeljković, Nikola AU - Dobričić, Vladimir AU - Bošković, Jelena AU - Vesović, Marina AU - Bradić, Jovana AU - Anđić, Marijana AU - Kočović, Aleksandar AU - Jeremić, Nevena AU - Novaković, Jovana AU - Jakovljević, Vladimir AU - Vujić, Zorica AU - Nikolić, Miloš PY - 2023 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5476 AB - The aim of the conducted study was to develop new potential dual COX-2 and 5-LOX inhibitors based on naproxen scaffold. We performed the evaluation of in vivo and in vitro anti-inflammatory activity of newly synthesized thiourea derivatives of naproxen containing m-anisidine and N-methyl tryptophan methyl ester in a side chain. An in vivo study was carried out using a carrageenan-induced paw edema model of acute inflammation. COX-2 and 5-LOX inhibitory potential of synthesized compounds was evaluated using fluorometric inhibitor screening kits. In silico study was performed in OEDocking 3.2.0.2 software with the FRED tool. Two investigated derivatives exhibited comparable anti-inflammatory activity to naproxen (56.32%) four hours after injection of carrageenan, with the percentage of inhibition being 54.01% (m-anisidine derivative) and 54.12% (N-methyl tryptophan methyl ester derivative). In vitro studies of COX-2 inhibition demonstrated that none of the tested compounds achieved 50% inhibition at concentrations below 100 μM, whereas the m-anisidine derivative accomplished comparable inhibition of 5-LOX (IC50 = 0.30 μM) to commercial 5-LOX inhibitor zileuton (IC50 = 0.36 μM). Inability of the tested compounds to form three hydrogen bonds with ARG120 and TYR355 could be a reason why these compounds showed weak COX-2 inhibition. The m-anisidine derivative formed a more stable complex with the 5-LOX enzyme (−8.39 kcal/mol), compared to N-methyl tryptophan methyl ester derivative (−7.98 kcal/mol), with the absence of the iron ion chelation in the active site in both cases. The significant in vivo anti-inflammatory activity of the m-anisidine derivative, together with the potent inhibition of 5-LOX, highlighted this compound as a promising anti-inflammatory agent. PB - Fakultet medicinskih nauka Univerziteta u Kragujevcu C3 - 9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia T1 - Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach UR - https://hdl.handle.net/21.15107/rcub_farfar_5476 ER -
@conference{ author = "Nedeljković, Nikola and Dobričić, Vladimir and Bošković, Jelena and Vesović, Marina and Bradić, Jovana and Anđić, Marijana and Kočović, Aleksandar and Jeremić, Nevena and Novaković, Jovana and Jakovljević, Vladimir and Vujić, Zorica and Nikolić, Miloš", year = "2023", abstract = "The aim of the conducted study was to develop new potential dual COX-2 and 5-LOX inhibitors based on naproxen scaffold. We performed the evaluation of in vivo and in vitro anti-inflammatory activity of newly synthesized thiourea derivatives of naproxen containing m-anisidine and N-methyl tryptophan methyl ester in a side chain. An in vivo study was carried out using a carrageenan-induced paw edema model of acute inflammation. COX-2 and 5-LOX inhibitory potential of synthesized compounds was evaluated using fluorometric inhibitor screening kits. In silico study was performed in OEDocking 3.2.0.2 software with the FRED tool. Two investigated derivatives exhibited comparable anti-inflammatory activity to naproxen (56.32%) four hours after injection of carrageenan, with the percentage of inhibition being 54.01% (m-anisidine derivative) and 54.12% (N-methyl tryptophan methyl ester derivative). In vitro studies of COX-2 inhibition demonstrated that none of the tested compounds achieved 50% inhibition at concentrations below 100 μM, whereas the m-anisidine derivative accomplished comparable inhibition of 5-LOX (IC50 = 0.30 μM) to commercial 5-LOX inhibitor zileuton (IC50 = 0.36 μM). Inability of the tested compounds to form three hydrogen bonds with ARG120 and TYR355 could be a reason why these compounds showed weak COX-2 inhibition. The m-anisidine derivative formed a more stable complex with the 5-LOX enzyme (−8.39 kcal/mol), compared to N-methyl tryptophan methyl ester derivative (−7.98 kcal/mol), with the absence of the iron ion chelation in the active site in both cases. The significant in vivo anti-inflammatory activity of the m-anisidine derivative, together with the potent inhibition of 5-LOX, highlighted this compound as a promising anti-inflammatory agent.", publisher = "Fakultet medicinskih nauka Univerziteta u Kragujevcu", journal = "9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia", title = "Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach", url = "https://hdl.handle.net/21.15107/rcub_farfar_5476" }
Nedeljković, N., Dobričić, V., Bošković, J., Vesović, M., Bradić, J., Anđić, M., Kočović, A., Jeremić, N., Novaković, J., Jakovljević, V., Vujić, Z.,& Nikolić, M.. (2023). Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach. in 9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia Fakultet medicinskih nauka Univerziteta u Kragujevcu.. https://hdl.handle.net/21.15107/rcub_farfar_5476
Nedeljković N, Dobričić V, Bošković J, Vesović M, Bradić J, Anđić M, Kočović A, Jeremić N, Novaković J, Jakovljević V, Vujić Z, Nikolić M. Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach. in 9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia. 2023;. https://hdl.handle.net/21.15107/rcub_farfar_5476 .
Nedeljković, Nikola, Dobričić, Vladimir, Bošković, Jelena, Vesović, Marina, Bradić, Jovana, Anđić, Marijana, Kočović, Aleksandar, Jeremić, Nevena, Novaković, Jovana, Jakovljević, Vladimir, Vujić, Zorica, Nikolić, Miloš, "Selected thiourea derivatives of naproxen as potential anti-inflammatory agents: in vivo, in vitro, and in silico approach" in 9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation, July 4th - 6th, 2023. Belgrade, Serbia (2023), https://hdl.handle.net/21.15107/rcub_farfar_5476 .