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Synthesis, Molecular Docking and Molecular Dynamics Simulation Studies of Some Pyridazinone Derivatives as Lipase Inhibitors

Year 2022, Volume 43, Issue 3, 391 - 397, 30.09.2022
https://doi.org/10.17776/csj.1135400

Abstract

Human health and illness are dependent on lipases, which play a key role in maintaining cell integrity, storing fat for energy and serving as signaling molecules. In this study, 4 compounds that carry 6-phenylpyridazin-3(2H)-one main nucleus, which can be effective as lipase inhibitors, were synthesized and their structures were elucidated. The biological activity of synthesized compounds was evaluated via the porcine pancreatic lipase type II (PLL) inhibitor assay. Orlistat, a lipase inhibitor, was used as a positive control. Compound 8d was found to be the most effective compound, with an IC50 value of 32.66±2.8265 (μg/mL). In addition, molecular docking and molecular dynamics simulations studies were carried out to examine the interactions of the compounds with the target in detail. The results obtained as a result of these in silico studies were found to be compatible with the lipase inhibition effects of the compounds. It was observed that the compounds may have potential lipase inhibitory effects as a result of the substitutions of the 3-(6-oxo-3-phenylpyridazin-1(6H)-yl)propanehydrazide structure.

References

  • [1] Tang Q.J., Zhang L., Zheng J., Song J., Chen X., Cao W., Xue C., He X., Ma M., Zhao Y., Drug-guided screening for pancreatic lipase inhibitors in functional foods, Food Funct, 12 (2021) 4644-4653.
  • [2] Zechner R., Zimmermann R., Eichmann T.O., Kohlwein S.D., Haemmerle G., Lass A. Madeo F., Fat Signals lipases and lipolysis in lipid metabolism and signaling, Cell metab., 15(2012) 279–291.
  • [3] Bachovchin D.A., Cravatt B.F., The pharmacological landscape and therapeutic potential of serine hydrolases, Nat Rev Drug Discov., 3 (2012) 52-68.
  • [4] Faucher F., Bennett J.M., Bogyo M., Lovell, S., Strategies for Tuning the Selectivity of Chemical Probes that Target Serine Hydrolases, Cell Chem. Biol, 27 (2020) 937-952.
  • [5] Ahmad E.M., Kassab A.E., El-Malah A.A., Hassan M.S.A., Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents, Eur. J. Med. Chem., 171 (2019) 25-37.
  • [6] Gong J., Zheng Y., Wang Y., Sheng W., Li Y., Liu, X. A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway, PLoS ONE, 13 (2018) e0191984.
  • [7] Ramadan S.K., Shaban S.S., Hashem A.I., Facile and expedient synthesis and anti-proliferative activity of diversely pyrrolones bearing 1,3-diphenylpyrazole moiety, Synth. Commun., 55 (2020) 185-196.
  • [8] Dubey S., Bhosle P.A., Pyridazinone: An important element of pharmacophore possessing broad spectrum of activity, Med. Chem. Res., 24 (2015) 3579-3598.
  • [9] Özdemir Z., Başak-Türkmen N., Ayhan İ., Çiftçi O., Uysal M., Synthesis of new 6-[4-(2-fluorophenylpiperazine-1-yl)]-3(2H)-pyridazinone-2-acethyl-2-(substitutedbenzal) hydrazine derivatives and evaluation of their cytotoxic effects in liver and colon cancer cell lines, Pharm. Chem. J., 52 (2019) 923–929.
  • [10] Ciftci O., Özdemir Z., Acar C., Sözen M., Başak-Türkmen N., Ayhan İ., Gözükara H., The novel synthesized pyridazinone derivates had the antiproliferative and apoptotic effects in SHSY5Y and HEP3B cancer cell line, Lett. Org. Chem., 15 (2018) 323–33.
  • [11] Asif M., Abid Imran M., Study of heterocyclic-fused pyridazinone analogues having phosphodiestrase-IV inhibitor activities as anti-inflammatory agents, J. Med. Chem. Sci., 3 (2020) 109-117.
  • [12] Alagöz M.A., Özdemir Z., Uysal M., Carradori S., Gallorini M., Ricci A., Zara S., Mathew B., Synthesis, Cytotoxicity and Anti-Proliferative Activity against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker, Pharmaceuticals, 14 (2021) 183.
  • [13] Önkol T., Gökçe M., Orhan İ., Kaynak F., Design, synthesis and evaluation of some novel 3(2H)-pyridazinone-2-yl acetohydrazides as acetylcholinesterase and butyrylcholnesterase inhibitors, Org. Commun., 6 (2013) 55-67.
  • [14] Özçelik A.B., Gökçe M., Orhan İ., Kaynak F., Şahin, M.F., Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory avtivities of novel ester and hydrazide derivatives of 3(2H)-pyridazinone, Arzneim.-Forschung, 60 (2010), 452-458.
  • [15] Bozbey İ., Özdemir Z., Uslu H., Özçelik A.B., Şenol F.S., Erdoğan-Orhan İ., Uysal, M., Mini Rev Med Chem, 20 (2020) 1042.
  • [16] Özdemir Z., Yılmaz H., Sarı S., Karakurt A., Şenol F.S., Uysal M., Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors, Med. Chem. Res., 26 (2017), 2293-308.
  • [17] Özçelik A.B., Özdemir Z., Sari S., Utku S., Uysal, M., A New Series of Pyridazinone Derivatives as Cholinesterases Inhibitors: Synthesis, In Vitro Activity and Molecular Modeling Studies, Pharmacol Rep., 71 (2019) 1253-1263.
  • [18] Kopelman P., Bryson A., Hickling R., Rissanen A., Rossner S., Toubro S., Valensi P., Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients, Int. J. Obes., 31 (2007) 494–499.
  • [19] Point V., Kumar K.V.P.P., Marc S., Delorme V., Parsiegla G., Amara S., Carri`ere F., Buono G., Fotiadu F., Canaan S., Leclaire J., Cavalier J.F., Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones, Eur. J. Med. Chem. 58 (2012) 452–463.
  • [20] Jayanna N.D., Vagdevi H.M., Dharshan J.C., Kekuda T.R.P., Hanumanthappa B. C., Gowdarshivannanavar B.C., Synthesis and biological evaluation of novel 5,7-dichloro-1,3-benzoxazole derivatives, J. Chem. 2013 (2012) 1–9.
  • [21] Kumar A., Chauhan S., Pancreatic lipase inhibitors: The road voyaged and successes, Life Sci., 271 (2021) 119115.
  • [22] Mentes E., Karaali N., Yilmaz F., Ülker S., Kahveci B., Microwave-assisted synthesis and biological evaluation of some benzimidazole derivatives containing a 1,2,4-triazol ring, Arch. Pharm., 346 (2013) 556–561.
  • [23] Bekircan O., Mentes E., Ülker S., Kucuk C., Synthesis of some new 1,2,4-triazole derivatives starting from 3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4- triazol with anti-lipase and anti-urease activities, Arch. Pharm. 347 (2014) 387–397.
  • [24] Evren A.E., Çelik İ., Acar Çevik U., Synthesis, molecular docking, in silico ADME and antimicrobial activity studies of some new benzimidazole-triazole derivatives, CSJ, 42 (2021) 795-805.
  • [25] Sridhar S.N.C., Bhurta D., Kantiwal D., George G., Monga V., Paul A.T., Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors, Bioorganic Med. Chem. Lett., 27 (2017) 3749-3754.
  • [26] Foteini-Nafsika D., Luis A.M., Angel G., Barrie K., Steve P.W., Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2, Platelets, 32 (2021) 744-752.
  • [27] Bivi N., Hu H., Chavali B., Chalmers M.J., Reutter C.T., Durst G.L., Riley A., Sato M., Allen M.R., Burr D.B., Dodge J.A., Structural features underlying raloxifene’s biophysical interaction with bone matrix, Bioorganic Med. Chem., 24 (2016) 759-767.
  • [28] Sable R., Jois S. Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors, Molecules, 20 (2015) 11569-11603.
  • [29] Hu B., Cui F., Yin F., Sun Y., Li Y., Caffeoylquinic Acids Competitively Inhibit Pancreatic Lipase through Binding to the Catalytic Triad, Int. J. Biol. Macromol., 80 (2015) 529-535.
  • [30] Halgren T., Murphy R., Friesner R., Beard H., Frye L., Pollard W., Banks J., Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening, J. Med. Chem., 47 (2004). 1750-1759.
  • [31] Kuzu B., Hepokur C., Alagöz M.A., Burmaoglu S., Algul O., Synthesis, Biological Evaluation and In Silico Studies of Some 2-Substituted Benzoxazole Derivatives as Potential Anticancer Agents to Breast Cancer, Chemistry Select, 7 (2022) e20210355.
  • [32] Ersan R.H., Kuzu B., Yetkin D., Alagoz M.A., Dogen A., Burmaoglu S., Algul O., 2-Phenyl substituted Benzimidazole derivatives: Design, synthesis, and evaluation of their antiproliferative and antimicrobial activities, Med. Chem. Res., (2022)
  • [33] Kolinski A., Klein P., Romiszowski P., Skolnick J., Unfolding of globular proteins: monte carlo dynamics of a realistic reduced model, Biophys. J, 85 (2003) 3271–3278.

Year 2022, Volume 43, Issue 3, 391 - 397, 30.09.2022
https://doi.org/10.17776/csj.1135400

Abstract

References

  • [1] Tang Q.J., Zhang L., Zheng J., Song J., Chen X., Cao W., Xue C., He X., Ma M., Zhao Y., Drug-guided screening for pancreatic lipase inhibitors in functional foods, Food Funct, 12 (2021) 4644-4653.
  • [2] Zechner R., Zimmermann R., Eichmann T.O., Kohlwein S.D., Haemmerle G., Lass A. Madeo F., Fat Signals lipases and lipolysis in lipid metabolism and signaling, Cell metab., 15(2012) 279–291.
  • [3] Bachovchin D.A., Cravatt B.F., The pharmacological landscape and therapeutic potential of serine hydrolases, Nat Rev Drug Discov., 3 (2012) 52-68.
  • [4] Faucher F., Bennett J.M., Bogyo M., Lovell, S., Strategies for Tuning the Selectivity of Chemical Probes that Target Serine Hydrolases, Cell Chem. Biol, 27 (2020) 937-952.
  • [5] Ahmad E.M., Kassab A.E., El-Malah A.A., Hassan M.S.A., Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents, Eur. J. Med. Chem., 171 (2019) 25-37.
  • [6] Gong J., Zheng Y., Wang Y., Sheng W., Li Y., Liu, X. A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway, PLoS ONE, 13 (2018) e0191984.
  • [7] Ramadan S.K., Shaban S.S., Hashem A.I., Facile and expedient synthesis and anti-proliferative activity of diversely pyrrolones bearing 1,3-diphenylpyrazole moiety, Synth. Commun., 55 (2020) 185-196.
  • [8] Dubey S., Bhosle P.A., Pyridazinone: An important element of pharmacophore possessing broad spectrum of activity, Med. Chem. Res., 24 (2015) 3579-3598.
  • [9] Özdemir Z., Başak-Türkmen N., Ayhan İ., Çiftçi O., Uysal M., Synthesis of new 6-[4-(2-fluorophenylpiperazine-1-yl)]-3(2H)-pyridazinone-2-acethyl-2-(substitutedbenzal) hydrazine derivatives and evaluation of their cytotoxic effects in liver and colon cancer cell lines, Pharm. Chem. J., 52 (2019) 923–929.
  • [10] Ciftci O., Özdemir Z., Acar C., Sözen M., Başak-Türkmen N., Ayhan İ., Gözükara H., The novel synthesized pyridazinone derivates had the antiproliferative and apoptotic effects in SHSY5Y and HEP3B cancer cell line, Lett. Org. Chem., 15 (2018) 323–33.
  • [11] Asif M., Abid Imran M., Study of heterocyclic-fused pyridazinone analogues having phosphodiestrase-IV inhibitor activities as anti-inflammatory agents, J. Med. Chem. Sci., 3 (2020) 109-117.
  • [12] Alagöz M.A., Özdemir Z., Uysal M., Carradori S., Gallorini M., Ricci A., Zara S., Mathew B., Synthesis, Cytotoxicity and Anti-Proliferative Activity against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker, Pharmaceuticals, 14 (2021) 183.
  • [13] Önkol T., Gökçe M., Orhan İ., Kaynak F., Design, synthesis and evaluation of some novel 3(2H)-pyridazinone-2-yl acetohydrazides as acetylcholinesterase and butyrylcholnesterase inhibitors, Org. Commun., 6 (2013) 55-67.
  • [14] Özçelik A.B., Gökçe M., Orhan İ., Kaynak F., Şahin, M.F., Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory avtivities of novel ester and hydrazide derivatives of 3(2H)-pyridazinone, Arzneim.-Forschung, 60 (2010), 452-458.
  • [15] Bozbey İ., Özdemir Z., Uslu H., Özçelik A.B., Şenol F.S., Erdoğan-Orhan İ., Uysal, M., Mini Rev Med Chem, 20 (2020) 1042.
  • [16] Özdemir Z., Yılmaz H., Sarı S., Karakurt A., Şenol F.S., Uysal M., Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors, Med. Chem. Res., 26 (2017), 2293-308.
  • [17] Özçelik A.B., Özdemir Z., Sari S., Utku S., Uysal, M., A New Series of Pyridazinone Derivatives as Cholinesterases Inhibitors: Synthesis, In Vitro Activity and Molecular Modeling Studies, Pharmacol Rep., 71 (2019) 1253-1263.
  • [18] Kopelman P., Bryson A., Hickling R., Rissanen A., Rossner S., Toubro S., Valensi P., Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients, Int. J. Obes., 31 (2007) 494–499.
  • [19] Point V., Kumar K.V.P.P., Marc S., Delorme V., Parsiegla G., Amara S., Carri`ere F., Buono G., Fotiadu F., Canaan S., Leclaire J., Cavalier J.F., Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones, Eur. J. Med. Chem. 58 (2012) 452–463.
  • [20] Jayanna N.D., Vagdevi H.M., Dharshan J.C., Kekuda T.R.P., Hanumanthappa B. C., Gowdarshivannanavar B.C., Synthesis and biological evaluation of novel 5,7-dichloro-1,3-benzoxazole derivatives, J. Chem. 2013 (2012) 1–9.
  • [21] Kumar A., Chauhan S., Pancreatic lipase inhibitors: The road voyaged and successes, Life Sci., 271 (2021) 119115.
  • [22] Mentes E., Karaali N., Yilmaz F., Ülker S., Kahveci B., Microwave-assisted synthesis and biological evaluation of some benzimidazole derivatives containing a 1,2,4-triazol ring, Arch. Pharm., 346 (2013) 556–561.
  • [23] Bekircan O., Mentes E., Ülker S., Kucuk C., Synthesis of some new 1,2,4-triazole derivatives starting from 3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4- triazol with anti-lipase and anti-urease activities, Arch. Pharm. 347 (2014) 387–397.
  • [24] Evren A.E., Çelik İ., Acar Çevik U., Synthesis, molecular docking, in silico ADME and antimicrobial activity studies of some new benzimidazole-triazole derivatives, CSJ, 42 (2021) 795-805.
  • [25] Sridhar S.N.C., Bhurta D., Kantiwal D., George G., Monga V., Paul A.T., Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors, Bioorganic Med. Chem. Lett., 27 (2017) 3749-3754.
  • [26] Foteini-Nafsika D., Luis A.M., Angel G., Barrie K., Steve P.W., Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2, Platelets, 32 (2021) 744-752.
  • [27] Bivi N., Hu H., Chavali B., Chalmers M.J., Reutter C.T., Durst G.L., Riley A., Sato M., Allen M.R., Burr D.B., Dodge J.A., Structural features underlying raloxifene’s biophysical interaction with bone matrix, Bioorganic Med. Chem., 24 (2016) 759-767.
  • [28] Sable R., Jois S. Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors, Molecules, 20 (2015) 11569-11603.
  • [29] Hu B., Cui F., Yin F., Sun Y., Li Y., Caffeoylquinic Acids Competitively Inhibit Pancreatic Lipase through Binding to the Catalytic Triad, Int. J. Biol. Macromol., 80 (2015) 529-535.
  • [30] Halgren T., Murphy R., Friesner R., Beard H., Frye L., Pollard W., Banks J., Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening, J. Med. Chem., 47 (2004). 1750-1759.
  • [31] Kuzu B., Hepokur C., Alagöz M.A., Burmaoglu S., Algul O., Synthesis, Biological Evaluation and In Silico Studies of Some 2-Substituted Benzoxazole Derivatives as Potential Anticancer Agents to Breast Cancer, Chemistry Select, 7 (2022) e20210355.
  • [32] Ersan R.H., Kuzu B., Yetkin D., Alagoz M.A., Dogen A., Burmaoglu S., Algul O., 2-Phenyl substituted Benzimidazole derivatives: Design, synthesis, and evaluation of their antiproliferative and antimicrobial activities, Med. Chem. Res., (2022)
  • [33] Kolinski A., Klein P., Romiszowski P., Skolnick J., Unfolding of globular proteins: monte carlo dynamics of a realistic reduced model, Biophys. J, 85 (2003) 3271–3278.

Details

Primary Language English
Subjects Pharmacology and Pharmacy
Journal Section Natural Sciences
Authors

Mehmet Abdullah ALAGÖZ> (Primary Author)
INONU UNIVERSITY
0000-0001-5190-7196
Türkiye


İnci Selin DOĞAN>
KARADENİZ TEKNİK ÜNİVERSİTESİ
0000-0003-4949-1747
Türkiye


Sıla SENER>
SAĞLIK BİLİMLERİ ÜNİVERSİTESİ, GÜLHANE ECZACILIK FAKÜLTESİ, GÜLHANE ECZACILIK PR.
0000-0001-7679-7165
Türkiye


Zeynep ÖZDEMİR>
İNÖNÜ ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ
0000-0003-4559-2305
Türkiye

Publication Date September 30, 2022
Application Date June 24, 2022
Acceptance Date August 26, 2022
Published in Issue Year 2022, Volume 43, Issue 3

Cite

APA Alagöz, M. A. , Doğan, İ. S. , Sener, S. & Özdemir, Z. (2022). Synthesis, Molecular Docking and Molecular Dynamics Simulation Studies of Some Pyridazinone Derivatives as Lipase Inhibitors . Cumhuriyet Science Journal , 43 (3) , 391-397 . DOI: 10.17776/csj.1135400