Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors:
Design, Synthesis and Biological Evaluation

Reema    Abu    Khalaf; Shorooq       Alqazaqi; Maram       Aburezeq; Dima       Sabbah; Ghadeer       Albadawi; Ghassan    Abu    Sheikha

doi:10.2174/1573409916666201007124122

Abstract

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein, and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduce the deterioration of gutderived endogenous incretin hormones secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of the pancreas.

Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities against the DPP-IV enzyme.

Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed.

Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 μM concentration, where compound 3d harboring ortho- fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669, and Y752 backbones

Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Keywords: Diabetes, dipeptidyl peptidase-IV, inhibitors, phenanthridine, sulfonamide, QPLD.

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[1] 
Blair, M. Diabetes Mellitus. Urol. Nurs.,  2016, 36(1), 27-36.
[http://dx.doi.org/10.7257/1053-816X.2016.36.1.27] [PMID:  27093761] 
[2] 
Punthakee, Z.; Goldenberg, R.; Katz, P. Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Can. J. Diabetes,  2018, 42(Suppl. 1), S10-S15.
[http://dx.doi.org/10.1016/j.jcjd.2017.10.003] [PMID:  29650080] 
[3] 
International Diabetes Federation IDF, 2018.
[4] 
International Diabetes Federation In: In: IDF DIABETES ATLAS, 8th ed; , 2017. 
[5] 
Cho, N.H.; Shaw, J.E.; Karuranga, S.; Huang, Y.; da Rocha Fernandes, J.D.; Ohlrogge, A.W.; Malanda, B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract.,  2018, 138, 271-281.
[http://dx.doi.org/10.1016/j.diabres.2018.02.023] [PMID:  29496507] 
[6] 
Paschou, S.A.; Papadopoulou-Marketou, N.; Chrousos, G.P.; Kanaka-Gantenbein, C. On type 1 diabetes mellitus pathogenesis. Endocr. Connect.,  2018, 7(1), R38-R46.
[http://dx.doi.org/10.1530/EC-17-0347] [PMID:  29191919] 
[7] 
DiMeglio, L.A.; Evans-Molina, C.; Oram, R.A. Type 1 diabetes. Lancet,  2018, 391(10138), 2449-2462.
[http://dx.doi.org/10.1016/S0140-6736(18)31320-5] [PMID:  29916386] 
[8] 
Saberzadeh-Ardestani, B.; Karamzadeh, R.; Basiri, M.; Hajizadeh-Saffar, E.; Farhadi, A.; Shapiro, A.M.J.; Tahamtani, Y.; Baharvand, H. Type 1 Diabetes Mellitus: Cellular and Molecular Pathophysiology at A Glance. Cell J.,  2018, 20(3), 294-301.
[PMID:  29845781] 
[9] 
World health organization. WHO; 2017. Available from: https://
www.who.int/gho/publications/world_health_statistics/
2017/EN_WHS2017_TOC.pdf
[10] 
Chatterjee, S.; Khunti, K.; Davies, M.J. Type 2 diabetes. Lancet,  2017, 389(10085), 2239-2251.
[http://dx.doi.org/10.1016/S0140-6736(17)30058-2] [PMID:  28190580] 
[11] 
American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes. Diabetes Care,  2018, 41(Suppl. 1), S13-S27.
[http://dx.doi.org/10.2337/dc18-S002] [PMID:  29222373] 
[12] 
Donazar-Ezcurra, M.; López-Del Burgo, C.; Bes-Rastrollo, M. Primary prevention of gestational diabetes mellitus through nutritional factors: a systematic review. BMC Pregnancy Childbirth,  2017, 17(1), 30.
[http://dx.doi.org/10.1186/s12884-016-1205-4] [PMID:  28086820] 
[13] 
Baynes, H.W. Classification, pathophysiology, diagnosis and management of diabetes mellitus. J. Diabetes Metab.,  2015, 6, 541.
[14] 
Houlden, R.L. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can. J. Diabetes,  2018, 42, S1-S325.
[http://dx.doi.org/10.1016/j.jcjd.2017.10.001] [PMID:  29650079] 
[15] 
Dendup, T.; Feng, X.; Clingan, S.; Astell-Burt, T. Environmental Risk Factors for Developing Type 2 Diabetes Mellitus: A Systematic Review. Int. J. Environ. Res. Public Health,  2018, 15(1), 78.
[http://dx.doi.org/10.3390/ijerph15010078] [PMID:  29304014] 
[16] 
Bellou, V.; Belbasis, L.; Tzoulaki, I.; Evangelou, E. Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses. PLoS One,  2018, 13(3), e0194127.
[http://dx.doi.org/10.1371/journal.pone.0194127] [PMID:  29558518] 
[17] 
Herder, C.; Schmitt, A.; Budden, F.; Reimer, A.; Kulzer, B.; Roden, M.; Haak, T.; Hermanns, N. Longitudinal associations between biomarkers of inflammation and changes in depressive symptoms in patients with type 1 and type 2 diabetes. Psychoneuroendocrinology,  2018, 91, 216-225.
[http://dx.doi.org/10.1016/j.psyneuen.2018.02.032] [PMID:  29525039] 
[18] 
Aschner, P.M.; Muñoz, O.M.; Girón, D.; García, O.M.; Fernández-Ávila, D.G.; Casas, L.Á.; Bohórquez, L.F.; Arango, T. C.M.; Carvajal, L.; Ramírez, D.A.; Sarmiento, J.G.; Colon, C.A.; Correa G, N.F.; Alarcón R, P.; Bustamante S, Á.A. Clinical practice guideline for the prevention, early detection, diagnosis, management and follow up of type 2 diabetes mellitus in adults. Colomb. Med.,  2016, 47(2), 109-131.
[http://dx.doi.org/10.25100/cm.v47i2.2207] [PMID:  27546934] 
[19] 
Zheng, Y.; Ley, S.H.; Hu, F.B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol.,  2018, 14(2), 88-98.
[http://dx.doi.org/10.1038/nrendo.2017.151] [PMID:  29219149] 
[20] 
Papatheodorou, K.; Banach, M.; Bekiari, E.; Rizzo, M.; Edmonds, M. Complications of Diabetes 2017. J. Diabetes Res.,  2018, 20183086167.
[http://dx.doi.org/10.1155/2018/3086167] [PMID:  29713648] 
[21] 
Lean, M.E.; Leslie, W.S.; Barnes, A.C.; Brosnahan, N.; Thom, G.; McCombie, L.; Peters, C.; Zhyzhneuskaya, S.; Al-Mrabeh, A.; Hollingsworth, K.G.; Rodrigues, A.M.; Rehackova, L.; Adamson, A.J.; Sniehotta, F.F.; Mathers, J.C.; Ross, H.M.; McIlvenna, Y.; Stefanetti, R.; Trenell, M.; Welsh, P.; Kean, S.; Ford, I.; McConnachie, A.; Sattar, N.; Taylor, R. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet,  2018, 391(10120), 541-551.
[http://dx.doi.org/10.1016/S0140-6736(17)33102-1] [PMID:  29221645] 
[22] 
Davis, A.; Kuriakose, J.; Clements, J.N. Faster Insulin Aspart: A New Bolus Option for Diabetes Mellitus. Clin. Pharmacokinet.,  2019, 58(4), 421-430.
[http://dx.doi.org/10.1007/s40262-018-0696-8] [PMID:  29978361] 
[23] 
Hosomura, N.; Malmasi, S.; Timerman, D.; Lei, V.J.; Zhang, H.; Chang, L.; Turchin, A. Decline of insulin therapy and delays in insulin initiation in people with uncontrolled diabetes mellitus. Diabet. Med.,  2017, 34(11), 1599-1602.
[http://dx.doi.org/10.1111/dme.13454] [PMID:  28905434] 
[24] 
Lipska, K.J.; Hirsch, I.B.; Riddle, M.C. Human Insulin for Type 2 Diabetes: An Effective, Less-Expensive Option. JAMA,  2017, 318(1), 23-24.
[http://dx.doi.org/10.1001/jama.2017.6939] [PMID:  28604935] 
[25] 
Home, P.D. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes. Metab.,  2015, 17(11), 1011-1020.
[http://dx.doi.org/10.1111/dom.12501] [PMID:  26041603] 
[26] 
Chaudhury, A.; Duvoor, C.; Reddy Dendi, V.S.; Kraleti, S.; Chada, A.; Ravilla, R.; Marco, A.; Shekhawat, N.S.; Montales, M.T.; Kuriakose, K.; Sasapu, A.; Beebe, A.; Patil, N.; Musham, C.K.; Lohani, G.P.; Mirza, W. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front. Endocrinol. (Lausanne),  2017, 8, 6.
[http://dx.doi.org/10.3389/fendo.2017.00006] [PMID:  28167928] 
[27] 
Song, R. Mechanism of Metformin: A Tale of Two Sites. Diabetes Care,  2016, 39(2), 187-189.
[http://dx.doi.org/10.2337/dci15-0013] [PMID:  26798149] 
[28] 
Davidson, M.A.; Mattison, D.R.; Azoulay, L.; Krewski, D. Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit. Rev. Toxicol.,  2018, 48(1), 52-108.
[http://dx.doi.org/10.1080/10408444.2017.1351420] [PMID:  28816105] 
[29] 
Plissonnier, M.L.; Fauconnet, S.; Bittard, H.; Mougin, C.; Rommelaere, J.; Lascombe, I. Cell death and restoration of TRAIL-sensitivity by ciglitazone in resistant cervical cancer cells. Oncotarget,  2017, 8(64), 107744-107762.
[http://dx.doi.org/10.18632/oncotarget.22632] [PMID:  29296202] 
[30] 
Yasmin, S.; Jayaprakash, V. Thiazolidinediones and PPAR orchestra as antidiabetic agents: From past to present. Eur. J. Med. Chem.,  2017, 126, 879-893.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.020] [PMID:  27988463] 
[31] 
Wu, P.C.; Wu, V.C.; Lin, C.J.; Pan, C.F.; Chen, C.Y.; Huang, T.M.; Wu, C.H.; Chen, L.; Wu, C.J. Meglitinides increase the risk of hypoglycemia in diabetic patients with advanced chronic kidney disease: a nationwide, population-based study. Oncotarget,  2017, 8(44), 78086-78095.
[http://dx.doi.org/10.18632/oncotarget.17475] [PMID:  29100450] 
[32] 
Dawed, A.Y.; Zhou, K.; Pearson, E.R. Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents. Pharm. Genomics Pers. Med.,  2016, 9, 17-29.
[PMID:  27103840] 
[33] 
Sola, D.; Rossi, L.; Schianca, G.P.; Maffioli, P.; Bigliocca, M.; Mella, R.; Corlianò, F.; Fra, G.P.; Bartoli, E.; Derosa, G. Sulfonylureas and their use in clinical practice. Arch. Med. Sci.,  2015, 11(4), 840-848.
[http://dx.doi.org/10.5114/aoms.2015.53304] [PMID:  26322096] 
[34] 
Khunti, K.; Chatterjee, S.; Gerstein, H.C.; Zoungas, S.; Davies, M.J. Do sulphonylureas still have a place in clinical practice? Lancet Diabetes Endocrinol.,  2018, 6(10), 821-832.
[http://dx.doi.org/10.1016/S2213-8587(18)30025-1] [PMID:  29501322] 
[35] 
Marín-Peñalver, J.J.; Martín-Timón, I.; Sevillano-Collantes, C.; Del Cañizo-Gómez, F.J. Update on the treatment of type 2 diabetes mellitus. World J. Diabetes,  2016, 7(17), 354-395.
[http://dx.doi.org/10.4239/wjd.v7.i17.354] [PMID:  27660695] 
[36] 
Joshi, S.R.; Standl, E.; Tong, N.; Shah, P.; Kalra, S.; Rathod, R. Therapeutic potential of α-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin. Pharmacother.,  2015, 16(13), 1959-1981.
[http://dx.doi.org/10.1517/14656566.2015.1070827] [PMID:  26255950] 
[37] 
Usman, B.; Sharma, N.; Satija, S.; Mehta, M.; Vyas, M.; Khatik, G.L.; Khurana, N.; Hansbro, P.M.; Williams, K.; Dua, K. Recent Developments in Alpha-Glucosidase Inhibitors for Management of Type-2 Diabetes: An Update. Curr. Pharm. Des.,  2019, 25(23), 2510-2525.
[http://dx.doi.org/10.2174/1381612825666190717104547] [PMID:  31333110] 
[38] 
Katsiki, N.; Mikhailidis, D.P.; Theodorakis, M.J. Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management. Curr. Pharm. Des.,  2017, 23(10), 1522-1532.
[http://dx.doi.org/10.2174/1381612823666170113152742] [PMID:  28088910] 
[39] 
Liu, X.Y.; Zhang, N.; Chen, R.; Zhao, J.G.; Yu, P. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years. J. Diabetes Complications,  2015, 29(8), 1295-1303.
[http://dx.doi.org/10.1016/j.jdiacomp.2015.07.011] [PMID:  26365905] 
[40] 
Ohkura, T. Ipragliflozin: A novel sodium-glucose cotransporter 2 inhibitor developed in Japan. World J. Diabetes,  2015, 6(1), 136-144.
[http://dx.doi.org/10.4239/wjd.v6.i1.136] [PMID:  25685284] 
[41] 
Aranias, T.; Grosfeld, A.; Poitou, C.; Omar, A.A.; Le Gall, M.; Miquel, S.; Garbin, K.; Ribeiro, A.; Bouillot, J.L.; Bado, A.; Brot-Laroche, E.; Clément, K.; Leturque, A.; Guilmeau, S.; Serradas, P. Lipid-rich diet enhances L-cell density in obese subjects and in
mice through improved L-cell differentiation J. Nutr. Sci., 2015. 4, e22.
[http://dx.doi.org/10.1017/jns.2015.11] [PMID:  26157580] 
[42] 
Nauck, M.A.; Meier, J.J. Incretin hormones: Their role in health and disease. Diabetes Obes. Metab.,  2018, 20(Suppl. 1), 5-21.
[http://dx.doi.org/10.1111/dom.13129] [PMID:  29364588] 
[43] 
Deacon, C.F. Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides,  2018, 100, 150-157.
[http://dx.doi.org/10.1016/j.peptides.2017.10.011] [PMID:  29412814] 
[44] 
Prasad-Reddy, L.; Isaacs, D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context,  2015, 4212283.
[http://dx.doi.org/10.7573/dic.212283] [PMID:  26213556] 
[45] 
Rehfeld, J.F. The Origin and Understanding of the Incretin Concept. Front. Endocrinol. (Lausanne),  2018, 9, 387.
[http://dx.doi.org/10.3389/fendo.2018.00387] [PMID:  30061863] 
[46] 
Drucker, D.J. Deciphering metabolic messages from the gut drives therapeutic innovation: the 2014 Banting Lecture. Diabetes,  2015, 64(2), 317-326.
[http://dx.doi.org/10.2337/db14-1514] [PMID:  25614665] 
[47] 
Mulvihill, E.E.; Varin, E.M.; Gladanac, B.; Campbell, J.E.; Ussher, J.R.; Baggio, L.L.; Yusta, B.; Ayala, J.; Burmeister, M.A.; Matthews, D.; Bang, K.W.A.; Ayala, J.E.; Drucker, D.J. Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis. Cell Metab.,  2017, 25(1), 152-165.
[http://dx.doi.org/10.1016/j.cmet.2016.10.007] [PMID:  27839908] 
[48] 
Ahrén, B.; Atkin, S.L.; Charpentier, G.; Warren, M.L.; Wilding, J.P.H.; Birch, S.; Holst, A.G.; Leiter, L.A. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. Diabetes Obes. Metab.,  2018, 20(9), 2210-2219.
[http://dx.doi.org/10.1111/dom.13353] [PMID:  29766634] 
[49] 
Tran, K.L.; Park, Y.I.; Pandya, S.; Muliyil, N.J.; Jensen, B.D.; Huynh, K.; Nguyen, Q.T. Overview of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Patients with Type 2 Diabetes. Am. Health Drug Benefits,  2017, 10(4), 178-188.
[PMID:  28794822] 
[50] 
Li, Y.; Li, L.; Hölscher, C. Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev. Neurosci.,  2016, 27(7), 689-711.
[http://dx.doi.org/10.1515/revneuro-2016-0018] [PMID:  27276528] 
[51] 
Zilleßen, P.; Celner, J.; Kretschmann, A.; Pfeifer, A.; Racké, K.; Mayer, P. Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes. Sci. Rep.,  2016, 6, 23074.
[http://dx.doi.org/10.1038/srep23074] [PMID:  26983599] 
[52] 
Berger, J.P. SinhaRoy, R.; Pocai, A.; Kelly, T.M.; Scapin, G.; Gao, Y.D.; Pryor, K.A.D.; Wu, J.K.; Eiermann, G.J.; Xu, S.S.; Zhang, X.; Tatosian, D.A.; Weber, A.E.; Thornberry, N.A.; Carr, R.D. A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice. Endocrinol Diabetes Metab,  2017, 1(1), e00002.
[http://dx.doi.org/10.1002/edm2.2] [PMID:  30815539] 
[53] 
Arulmozhiraja, S.; Matsuo, N.; Ishitsubo, E.; Okazaki, S.; Shimano, H.; Tokiwa, H. Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs - An Ab Initio Fragment Molecular Orbital Study. PLoS One,  2016, 11(11), e0166275.
[http://dx.doi.org/10.1371/journal.pone.0166275] [PMID:  27832184] 
[54] 
Khalaf, R.A. Exploring Natural Products as a Source for Antidiabetic Lead Compounds and Possible Lead Optimization. Curr. Top. Med. Chem.,  2016, 16(23), 2549-2561.
[http://dx.doi.org/10.2174/1568026616666160414123602] [PMID:  27086794] 
[55] 
Marvaniya, H.M.; Patel, H.U. Role of dipeptidyl peptidase-IV (DPP-4) inhibitor in the management of type 2 diabetes. World J. Pharm. Pharm. Sci.,  2017, 6, 551-566.
[http://dx.doi.org/10.20959/wjpps20178-9797] 
[56] 
Perl, S.; Cook, W.; Wei, C.; Iqbal, N.; Hirshberg, B. Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes and Moderate Renal Impairment. Diabetes Ther.,  2016, 7(3), 527-535.
[http://dx.doi.org/10.1007/s13300-016-0184-9] [PMID:  27402391] 
[57] 
Sekar, R.; Singh, K.; Arokiaraj, A.W.; Chow, B.K. Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon. Int. Rev. Cell Mol. Biol.,  2016, 326, 279-341.
[http://dx.doi.org/10.1016/bs.ircmb.2016.05.002] [PMID:  27572131] 
[58] 
Schott, G.; Martinez, Y.V.; Ediriweera de Silva, R.E.; Renom-Guiteras, A.; Vögele, A.; Reeves, D.; Kunnamo, I.; Marttila-Vaara, M.; Sönnichsen, A. Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing. BMC Geriatr.,  2017, 17(Suppl. 1), 226.
[http://dx.doi.org/10.1186/s12877-017-0571-8] [PMID:  29047372] 
[59] 
Wang, T.; McNeill, A.M.; Chen, Y.; O’Neill, E.A.; Engel, S.S. Characteristics of Elderly Patients Initiating Sitagliptin or Non-DPP-4-Inhibitor Oral Antihyperglycemic Agents: Analysis of a Cross-Sectional US Claims Database. Diabetes Ther.,  2018, 9(1), 309-315.
[http://dx.doi.org/10.1007/s13300-017-0360-6] [PMID:  29330813] 
[60] 
Deacon, C.F.; Lebovitz, H.E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes. Metab.,  2016, 18(4), 333-347.
[http://dx.doi.org/10.1111/dom.12610] [PMID:  26597596] 
[61] 
Khalaf, R.A.; Sheikha, G.A.; Al-Sha’er, M.; Taha, M. Design, Synthesis and Biological Evaluation of N4-Sulfonamido-Succinamic, Phthalamic, Acrylic and Benzoyl Acetic Acid Derivatives as Potential DPP IV Inhibitors. Open Med. Chem. J.,  2013, 7, 39-48.
[http://dx.doi.org/10.2174/1874104501307010039] [PMID:  24358058] 
[62] 
Abu Khalaf, R.; Jarekji, Z.; Al-Qirim, T.; Sabbah, D.; Shattat, G. Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors. Can. J. Chem.,  2015, 93, 721-729.
[http://dx.doi.org/10.1139/cjc-2015-0039] 
[63] 
Khalaf, R.A.; Sabbah, D.; Al-Shalabi, E.; Al-Sheikh, I.; Albadawi, G.; Abu Sheikha, G. Synthesis, Structural Characterization and Docking Studies of Sulfamoyl- Phenyl Acid Esters as Dipeptidyl Peptidase-IV Inhibitors. Curr Comput Aided Drug Des,  2018, 14(2), 142-151.
[http://dx.doi.org/10.2174/1573409914666180308164013] [PMID:  29521244] 
[64] 
Abu Khalaf, R.; Masalha, D.; Sabbah, D. DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design, and Synthesis Curr; Comput. Aided Drug Des, 2020.  16(3), 295-307.
[65] 
Sutton, J.M.; Clark, D.E.; Dunsdon, S.J.; Fenton, G.; Fillmore, A.; Harris, N.V.; Higgs, C.; Hurley, C.A.; Krintel, S.L.; MacKenzie, R.E.; Duttaroy, A.; Gangl, E.; Maniara, W.; Sedrani, R.; Namoto, K.; Ostermann, N.; Gerhartz, B.; Sirockin, F.; Trappe, J.; Hassiepen, U.; Baeschlin, D.K. Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett.,  2012, 22(3), 1464-1468.
[http://dx.doi.org/10.1016/j.bmcl.2011.11.054] [PMID:  22177783] 
[66] 
Schrödinger. Protein Preparation Wizard, Maestro, Macromodel, QPLD-dock, and Pymol; Schrödinger, LLC: Portland, OR, U.S.A., 2016, p. 97204.
[67] 
Cho, A.E.; Guallar, V.; Berne, B.J.; Friesner, R. Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach. J. Comput. Chem.,  2005, 26(9), 915-931.
[http://dx.doi.org/10.1002/jcc.20222] [PMID:  15841474] 
[68] 
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem.,  2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID:  15027865] 
[69] 
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem.,  2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID:  17034125] 

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DOI https://dx.doi.org/10.2174/1573409916666201007124122	Print ISSN 1573-4099
Publisher Name Bentham Science Publisher	Online ISSN 1875-6697

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Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

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