In Silico Prediction of Binding Affinities of Hybrid Molecules of Benzothiazole Linked with Hydroxamic Acid by Disulfide Bond and Certain Linkers with HDAC8 Enzyme



  • Mayssam Hazem Pharmaceutical Chemistry Department, College of Pharmacy, Al-Mustanseryia University
  • Shakir M. Alwan Department of Pharmacy/ Al-Farabi University College



Benzothiazole, Amino acids, Molecular hybridization, Vorinostat, HDACs inhibitors


A new hybrid molecule of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid were synthesised. All the synthesized hybrid molecules (1-5) were subjected to molecular docking studies to evaluate their binding affinities with histone deacetylase enzyme (HDAC8, PDB ID: 1T69) and recorded lower ΔG (-8.276, -10.093, -8.647, -6.315, -8.676 kcal/mole, respectively) than the reference ligand (Vorinostat, suberoylanilide hydroxamic acid, SAHA -5.375 kcal/mole).

Molecular docking studies were performed using the maestro software (Schrödinger, version 2022-1). Moreover, compound 2, which is Benzothiazole-p-amino benzoic acid-hydroxamate has recorded the lowest binding score (-10.093). This may indicate that this compound is the most potent hybrid molecule. There were no violations from Lipinski’s rule and all the synthesized hybrid molecules comply with all parameters. Swiss ADME server was employed for the in silico molecular docking for prediction of the physicochemical and ADME properties of the investigated compounds. All hybrid molecules showed low possible passive oral absorption and no penetration into BBB. The hybrid molecules 1and 3 may be considered as P-gp substrates.


- Kumar A, Mishra AK. Advancement in pharmacological activities of benzothiazole and its derivatives: An up-to-date review. Mini Reviews in Medicinal Chemistry. 2021 Feb 1;21(3):314-35. doi: 10.2174/1389557520666200820133252

- Priyanka K. Azizur Md, Nishad S. Kumar S, Anas M, Mujahid M. Synthesis and biological activities of benzothiazole derivatives: A review. Intelligent Pharmacy.2023 Jun;1(3):122-132

- Ali SA. Synthesis and preliminary antibacterial study of new 2-mercapto-1, 3-benzothiazole derivatives with expected biological activity. AJPS13 (1). 2013.

- Dubey R, Shrivastava PK, Basniwal PK, Bhattacharya S, Narayana Moorthy NS. 2-(4-Aminophenyl) benzothiazole: a potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines. Mini reviews in medicinal chemistry. 2006 Jun 1;6(6):633-7. DOI: 10.2174/138955706777435706

- Shi DF, Bradshaw TD, Wrigley S, McCall CJ, Lelieveld P, Fichtner I, Stevens MF. Antitumor benzothiazoles. 3. Synthesis of 2-(4-aminophenyl) benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo. Journal of medicinal chemistry. 1996 Aug 16;39(17):3375-84. doi:10.1021/jm9600959.

- Mai A, Massa S, Lavu S, Pezzi R, Simeoni S, Ragno R, Mariotti FR, Chiani F, Camilloni G, Sinclair DA. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. Journal of medicinal chemistry. 2005 Dec 1;48(24):7789-95.. doi:10.1021/jm050100l

- Lewis KA, Jordan HR, Tollefsbol TO. Effects of SAHA and EGCG on growth potentiation of triple-negative breast cancer cells. Cancers. 2018 Dec 27;11(1):23.DOI:10.1158/1538-7755.DISP17-A67.

- Persky DO, Li H, Rimsza LM, Barr PM, Popplewell LL, Bane CL, Von Gehr A, LeBlanc M, Fisher RI, Smith SM, Friedberg JW. A phase I/II trial of vorinostat (SAHA) in combination with rituximab‐CHOP in patients with newly diagnosed advanced stage diffuse large B‐cell lymphoma (DLBCL): SWOG S0806. American journal of hematology. 2018 Aug;93(4):486-93. doi: 10.1002/ajh.25010.

- Mishra S, Singh P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. European journal of medicinal chemistry. 2016 Nov 29; 124:500-36.

- Musso L, Dallavalle S, Zunino F. Perspectives in the development of hybrid bifunctional antitumour agents. Biochemical Pharmacology. 2015 Aug 15;96(4):297-305.

- Papavassiliou KA, Papavassiliou AG. Histone deacetylases inhibitors: conjugation to other anti-tumour pharmacophores provides novel tools for cancer treatment. Expert opinion on investigational drugs. 2014 Mar 1;23(3):291-4.

- Alwan SM. Synthesis and preliminary antimicrobial activities of new arylideneamino-1, 3, 4-thiadiazole-(thio/dithio)-acetamido cephalosporanic acids. Molecules. 2012 Jan 19;17(1):1025-38. DOI: 10.3390/molecules17011025

- Bach RD, Dmitrenko O, Thorpe C. Mechanism of thiolate− disulfide interchange reactions in biochemistry. The Journal of organic chemistry. 2008 Jan 4;73(1):12-21. DOI: 10.1021/jo702051f

- Noguchi T, Sekine M, Yokoo Y, Jung S, Imai N. Convenient preparation of primary amides via activation of carboxylic acids with ethyl chloroformate and triethylamine under mild conditions. Chemistry Letters. 2013 Jun 5;42(6):580-2. DOI:10.1246/cl.130096.

- Daina A, Zoete V. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016 Jun 6;11(11):1117-21. DOI: 10.1002/cmdc.201600182.

- Mazen Mohammed Jwaid, Karima Fadhil Ali, Mayada Hadi Abd-alwahab. Synthesis, Antibacterial study and ADME Evaluation of Novel Isonicotinoyl Hydrazide Derivative Containing 1,3,4-Oxadiazole Moiety. Al Mustansiriyah J Pharm Sci. 2022;20(4):113–21

- Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein–ligand docking using GOLD. Proteins: Structure, Function, and Bioinformatics. 2003 Sep;52(4):609-23. DOI:10.1002/prot.10465.

- Muhsin YF, Alwan SM, Khan AK. Design, Molecular Docking, Synthesis of Aromatic Amino Acids Linked to Cephalexin. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2021;21(3):25-34.




How to Cite

Hazem, M., & Shakir M. Alwan. (2024). In Silico Prediction of Binding Affinities of Hybrid Molecules of Benzothiazole Linked with Hydroxamic Acid by Disulfide Bond and Certain Linkers with HDAC8 Enzyme : M. Al Mustansiriyah Journal of Pharmaceutical Sciences, 24(3), 274–283.