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Current Computer-Aided Drug Design


ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

In Silico Appraisal, Synthesis, Antibacterial Screening and DNA Cleavage for 1,2,5-thiadiazole Derivative

Author(s): Suraj N. Mali, Sudhir Sawant, Hemchandra K. Chaudhari* and Mustapha C. Mandewale

Volume 15 , Issue 5 , 2019

Page: [445 - 455] Pages: 11

DOI: 10.2174/1573409915666190206142756

Price: $65


Background: Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore.

Methods: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy.

Results: The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species.

Conclusion: In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field.

Keywords: Heterocycle, tuberculosis, DNA cleavage, molecular docking, thiadiazole, antibacterial.

Graphical Abstract
Mali, S.N.; Chaudhari, H.K. Computational studies on imidazo[1,2-a] Pyridine-3-Carboxamide analogues as antimycobacterial agents: common pharmacophore generation, atom-based 3D-QSAR, Molecular dynamics simulation, QikProp, molecular docking and prime MMGBSA approaches. Open Pharm. Sci. J., 2018, 5, 12-23.
Ali, A.A.A.; Lee, Y.R.; Chen, T.C.; Chen, C.L.; Lee, C.C.; Shiau, C.Y. Novel Anthra[1,2-c] [1,2,5]Thiadiazole-6,11-Diones as Promising anticancer lead compounds: Biological evaluation, characterization & molecular targets determination. PLoS One, 2016, 11(4)e0154278
Kushwaha, N.; Kushwaha, S.K.S.; Rai, A.K. Biological activities of thiadiazole derivatives: A review. Int. J. Chemtech Res., 2012, 4(2), 517-531.
Ismail, Z.H.; Ghorab, M.M.; Mohamed, E.M.A.; Aly, H.M.; El-Gaby, M.S.A. Antitumor activity of some novel 1,2,5-Thiadiazole derivatives. Phosphorus Sulfur, 2008, 183(10), 2541-2554.
Patel, J.Z. Optimization of 1,2,5-Thiadiazole Carbamates as Potent and Selective ABHD6 Inhibitors. ChemMedChem, 2015, 10(2), 253-265.
Dawood, K.M.; Farghaly, T.A. Thiadiazole inhibitors: A patent review. Expert Opin. Ther. Pat., 2017, 27(4), 477-505.
Biden, T.J.; Pearson, G.L. Method of treating glucose metabolism disorders comprisingan antagonist of lysosomal acid lipase either alone or in combination. PCT Int. Appl., WO2014000058 A1 20140103; 2014.
Rai, D. Chen, W.; Zhan, P. Synthesis and Anti-HIV activity of 4-(Naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives. Chem. Biol. Drug Des., 2014, 84, 420-430.
Biju, P.J.; Taveras, A.G.; Yu, Y. Preparation of diaminothiadiazoles as CXC- and CC-chemokine receptor ligands. PCT Int. Appl., WO 2005066147 A1 20050721, 2005
Volotinen, M.; Korjamo, T.; Tolonen, A.; Turpeinen, M.; Pelkonen, O.; Hakkola, J.; Mäenpää, J. Effects of selective serotonin reuptake inhibitors on timolol metabolism in human liver microsomes and cryo-preserved hepatocytes. Basic Clin. Pharmacol. Toxicol., 2010, 106(4), 302-309.
Glide. New York, NY; Schrodinger, LLC, 2017.
Schrödinger, L.L. Maestro, version 11.1; Schrödinger New York, NY, USA Release, 2017.
Qikprop. New York, NY; Schrodinger, LLC, 2017.
Prime. New York, NY; Schrodinger, LLC, 2017.
Ligprep. New York, NY; Schrodinger, LLC, 2017.
Friesner, R.A.; Banks, J.L.; Murphy, R.B. Glide: A new approach for rapid, accurate docking and scoring. J. Med. Chem., 2004, 47(7), 1739-1749.
Tosi, G.; Zironi, F.; Caselli, E.; Forni, A.; Prati, F. Biocatalytic Asymmetric Synthesis of (S)- and (R)-Timolol. Synthesis, 2004, 10, 1625-1628.
Wasson, B.K. 4-(3-secondary amino-2-hydroxy-proxy)-1,2,5- thiadiazoles. United States patent US 3,655,663 1972
Feixiong, C. AdmetSAR: A comprehensive source and free tool for evaluating chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
Gfeller, D.; Grosdidier, A.; Wirth, M.; Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: A webserver for target prediction of bioactive small molecules. Nucl. Acids Res., 2014, (Web Server issue) W32-W38.,
Hung, A.W.; Silvestre, H.L.; Wen, S.; Ciulli, A.; Blundell, T.L.; Abell, C. Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angew. Chem. Int. Ed. Engl., 2009, 48(45), 8452-8456.
Cho, S.; Lee, H.S.; Franzblau, S. Microplate alamar blue assay (MABA) and low oxygen recovery assay (LORA) for Mycobacterium tuberculosis. Methods Mol. Biol., 2015, 1285, 281-292.

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