Synthesis of Novel Triazinoindole-Based Thiourea Hybrid: A Study on α-Glucosidase Inhibitors and Their Molecular Docking

A new class of triazinoindole-bearing thiosemicarbazides (1–25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogs exhibited excellent inhibitory potential, with IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 μM when compared to standard acarbose (an IC50 value of 38.60 ± 0.20 μM). Among the series, analogs 1 and 23 were found to be the most potent, with IC50 values of 1.30 ± 0.05 and 1.30 ± 0.01 μM, respectively. The structure–activity relationship (SAR) was mainly based upon bringing about different substituents on the phenyl rings. To confirm the binding interactions, a molecular docking study was performed.

[1]  A. Rehman,et al.  Synthesis, in vitro urease inhibitory potential and molecular docking study of Benzimidazole analogues. , 2019, Bioorganic chemistry.

[2]  N. Uddin,et al.  Synthesis of new arylhydrazide bearing Schiff bases/thiazolidinone: α-Amylase, urease activities and their molecular docking studies. , 2019, Bioorganic chemistry.

[3]  H. Ullah,et al.  Synthesis, In vitro α-Glucosidase Inhibitory Potential and Molecular Docking Studies of 2-Amino-1,3,4-Oxadiazole Derivatives. , 2019, Medicinal chemistry (Shariqah (United Arab Emirates)).

[4]  H. Ullah,et al.  Synthesis of Bis-indolylmethane sulfonohydrazides derivatives as potent α-Glucosidase inhibitors. , 2018, Bioorganic chemistry.

[5]  H. Ullah,et al.  Synthesis, molecular docking study and in vitro thymidine phosphorylase inhibitory potential of oxadiazole derivatives. , 2018, Bioorganic chemistry.

[6]  H. Ullah,et al.  Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies. , 2018, Bioorganic & medicinal chemistry.

[7]  H. Ullah,et al.  Synthesis of bis-indolylmethanes as new potential inhibitors of β-glucuronidase and their molecular docking studies. , 2018, European journal of medicinal chemistry.

[8]  Faisal Nawaz,et al.  Synthesis of alpha amylase inhibitors based on privileged indole scaffold. , 2017, Bioorganic chemistry.

[9]  H. Ullah,et al.  Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide based Schiff bases. , 2016, Bioorganic chemistry.

[10]  H. Ullah,et al.  Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs. , 2016, Bioorganic chemistry.

[11]  H. Ullah,et al.  Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors. , 2016, Bioorganic & medicinal chemistry.

[12]  U. Rashid,et al.  Synthesis of 2-acylated and sulfonated 4-hydroxycoumarins: In vitro urease inhibition and molecular docking studies. , 2016, Bioorganic chemistry.

[13]  M. Bilal,et al.  Development of bis-thiobarbiturates as successful urease inhibitors and their molecular modeling studies , 2016 .

[14]  A. Hameed,et al.  Anti-cancer potential of benzophenone-bis-Schiff bases on human pancreatic cancer cell line , 2016 .

[15]  Syed Muhammad Kashif,et al.  Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies. , 2015, European journal of medicinal chemistry.

[16]  Qurat-Ul-Ain,et al.  Synthesis, molecular docking, acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease. , 2015, Bioorganic chemistry.

[17]  H. Ullah,et al.  Synthesis, in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase. , 2015, Bioorganic chemistry.

[18]  H. Ullah,et al.  Triazinoindole analogs as potent inhibitors of α-glucosidase: synthesis, biological evaluation and molecular docking studies. , 2015, Bioorganic chemistry.

[19]  S. Bodhankar,et al.  Effect of newly synthesized 1,2,4-triazino[5,6-b]indole-3-thione derivatives on olfactory bulbectomy induced depression in rats. , 2012, Asian Pacific journal of tropical biomedicine.

[20]  R. Kondo,et al.  Ganoderol B: a potent α-glucosidase inhibitor isolated from the fruiting body of Ganoderma lucidum. , 2011, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[21]  S. Bhosale,et al.  Synthesis, antidepressant evaluation and QSAR studies of novel 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides. , 2010, Bioorganic & medicinal chemistry letters.

[22]  K. Shimamoto,et al.  Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance , 2009, The Lancet.

[23]  K. Rother.  Diabetes treatment--bridging the divide. , 2007, The New England journal of medicine.

[24]  R. Ferraris,et al.  alpha-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice. , 2006, Metabolism: clinical and experimental.

[25]  T. Kuznetsova,et al.  Thiourea and thiosemicarbazide derivatives: Structure, transformations, and pharmacological activity. Part II. Antihypoxic activity of 1,2,4-triazino[5,6-b]indole derivatives , 1997, Pharmaceutical Chemistry Journal.

[26]  J. L. Kgokong,et al.  1,2,4-Triazino-[5,6b]indole derivatives: effects of the trifluoromethyl group on in vitro antimalarial activity. , 2005, Bioorganic & medicinal chemistry.

[27]  Markolf Hanefeld,et al.  Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. , 2003, JAMA.

[28]  V. Velezheva,et al.  Thiourea and Thiosemicarbazide Derivatives. Structure, Transformations and Pharmacological Activity. Part 5. Imidazo[4,5-b]indoles. , 1998 .

[29]  A. Monge,et al.  New 5H-1,2,4-triazino[5,6-b]indole and aminoindole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation, anti-hypertensive agents and thromboxane synthetase inhibitors , 1991 .

[30]  J. R. Hoover,et al.  The in Vitro Antiviral Activity of a Triazinoindole (SK&F 40491) , 1972, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[31]  J. J. Boyle,et al.  PROGRESS IN RHINOVIRUS CHEMOTHERAPY , 1970 .

[32]  J. M. Gwaltney,et al.  Rhinovirus Inhibition by 3-Substituted Triazinoindoles , 1970, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[33]  J. J. Boyle,et al.  Inhibition of Rhinovirus by Isatin Thiosemicarbazone Analogues , 1969, Nature.