Docking and Biological Screening of Bezo[A]phenothiazinones as Novel Inhibitors of Bacterial Peptidogloycan Transpeptidase

Document Type: Research Article

Authors

1 Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, NIGERIA

2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, California, USA.

3 Department of Pure and Industrial Chemistry, University of University, Nsukka, NIGERIA

Abstract

Rising cases of antibiotic-resistant bacteria is a public health concern. Many approved antibiotics target penicillin-binding proteins example peptidoglycan transpeptidase (PTPase). Due to wide pharmacological activity of phenothiazines, new styryl, aryl, alkynyl, and thiophenyl benzo[a]phenothiazines were synthesized and their inhibitory potency against PTPasein silico and Gram-positive/Gram-negative bacteria evaluated. The compounds inhibited the activity of PTPase at 18.93 - 75.48 µM and their best-docked poses identified interaction with PTPase Tyr318, His336, and His352. Experimental results agreed with computational predictions and further confirmed the benzo[a]phenothiazines as potential antibiotics. Also, the identified essential residues could be targeted during the rational optimization of the analogs.

Keywords

Main Subjects


[1] Laxminarayan R., Duse A., Wattal C., Zaidi A.K., Wertheim H.F., Sumpradit N., Vlieghe E., Hara G.L., Gould I.M., Goossens H., Greko C., So A.D., Bigdeli M., Tomson G., Woodhouse W., Ombaka E., Peralta A.Q., Qamar F.N., Mir F., Kariuki S., Bhutta Z.A., Coates A., Bergstrom R., Wright G.D., Brown E.D., Cars O., Antibiotic Resistance-the Need for Global Solutions, Lancet. Infect. Dis., 13: 1057–1098 (2013).
[2] Hoffman S.J., Outterson K., Røttingen J.A., Cars O., Clift C., Rizvi Z., Rotberg F., Tomson G., Zorzet A., An International Legal Framework to Address Antimicrobial Resistance, Bulletin of the World Health Organization, 93: 66-78 (2015).
[3] Franz A.W., Rominger F., Muller T.J.J., Synthesis and Electronic Properties of Stericallydemanding N-Arylphenothiazines and Unexpected Buchwald-Hartwigaminations, J. Org. Chem., 73: 1795-1804 (2008).
[4] Kumar N., Sharma A.K., Garg R., Yadav A.K., Antimicrobial Screening and Synthesis of Some Novel Benzo[a]phenothiazine and Rbofuransides, Indian J. Chem., 45B: 747-756(2006).
[5] Swarnkar P.K., Kriplani P., Gupta G.N., Ojha K.G., Synthesis and Antibacterial Activity of Some New Phenothiazine Derivatives, Elect. J. Chem., 4: 14–20 (2007).
[6] Mosnaim A.D., Ranade V.V., Wolf M.E., Puente J., Antonieta V.M., Phenothiazine Molecule Provides the Basic Chemical Structure for Various Classes of Pharmaco-Therapeutic Agents, Am. J. Ther., 13: 261-273 (2006).
[7] Arulmurugan S., Kavitha H.P., Synthesis, Characterization and Study of Antibacterial Activity of Some Novel Tetrazole Derivatives, Orbital. Electr. J. Chem., 2: 271-276 (2010).
[8] Pluta K., Morak-Miodawska B., Jelen M., Biological Activities of Synthesized Phenothiazines, Eur. J. Med. Chem. 46: 3179-3189 (2011).
[9] Motohashi N., Kurihara T., Yamanaka W., Satoh K., Sakagami H., Molnar J., Relationship between Biological Activity and Dipole Moment in Benzo[a]phenothiazines, Anticancer Research., 17: 3431-3435 (2011).
[10] Onoabedje E.A., Okoro U.C., Sarkar A., Knight D.W., Fuctionalization of Linear and Angular Phenothiazine and Phenoxazine Ring Systems via Pd(0)/Xphos Mediated Suzuki-Miyaura Cross-Coupling Reactions, J. Heterocyclic. Chem., 53: 1787 – 1794 (2016).
[11] Onoabedje E. A, Okoro U. C, Knight D. W., Rapid Access to New Angular Phenothiazine and Phenoxazine Dyes. J. Heterocyclic. Chem., 54: 206 – 214 (2017).
[12] Onoabedje E.A, Okoro U.C, Sarkar A, Knight D.W., Synthesis and Structure of New Alkynyl Derivatives of Phenothiazine and Phenoxazine, J. Sulfur Chem., 34: 269 – 281 (2016).
[13] Ntie-Kang F, Nwodo N. J, Ibezim A, Simoben C. V, Karaman B, Ngwa V. F, Sippl W, Adikwu M. U, Mbaze L. M., Molecular Modeling of Potential Anticancer Agents from African Medicinal Plants, J. Chem. Inf. Model., 54: 2433-2450 (2014).
[14] Onoabedje E. A, Ibezim A, Okafor S. N, Onoabedje U. S, Okoro U. C., Oxazin-5-Ones as a Novel Class of Penicillin Binding Protein Inhibitors: Design, Synthesis and Structure Activity Relationship, PLoS ONE., 11: 234-240 (2016).
[15] Ibezim E. A, Nwodo N. J, Nnaji J. N, Ujam O. T, Olubiyi O. O, Mba C. J., In-silico Investigation of Morpholines as Novel Class of Trypanosomal TriosephosphateIsomerase Inhibitors,  Med. Chem. Res. doi:10.1007/s00044-016-1739-z (2016).
[16] Ibezim E. A, Olujide O. O, Ata A. K, Mbah C. J, Nwodo N. J., Structure-based Design of Natural Products as Anti-Schistosoma Drug: Virtual Screening, Structure Activity Relationship and Molecular Dynamic Studies, Current Computer-aided Drug Design, 13: 91 – 100 (2017).
[17] Metuge J. A, Kang F. N, Fuhngwa V, Babiaka S. B, Samje M, Cho-Ngwa F., Molecular Modeling of Plant Metabolites with Anti-Onchocerca Activity, Med Chem Res., 24: 2127–2141 (2015).
[18] Banzhaf A. T. M, Gross C. A Vollmer W., From the Regulation of Peptidoglycan Synthesis to Bacterial Growth and Morphology, Nature Reviews., 10: 123-136 (2012).
[19] Kumar P., Kaushik A., Lloyd E.P., Li S.G., Mattoo R., Ammerman N.C., Bell D.T., Perryman A.L., Zandi T.A., Ekins S., Ginell S.L., Townsend C.A., Freundlich J.S., Lamichhane G., Non-Classical Transpeptidases Yield insight Into New Antibacterial,  Nat. Chem. Biol. 13: 54-61 (2017)
[20] Von-Rechenberg M, Blake B. K, Ho Y. S, Zhen Y, Chepanoske C. L, Richardson B. E, Xu N, Kery V.,  Ampicillin/Penicillin-Binding Protein Interactions as a Model Drug-Target System to Optimize Affinity Pull-down and Mass Spectrometric Strategies for Target and Pathway Identification, Proteomics., 5: 1764-7173 (2005).
[21] Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J., Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings, Adv. Drug. Deliv. Rev., 23: 3–25 (1997).
[22] Pluta K., Morak-Miodawska B., Jelen M., Recent Progress in Biological Activity of Synthesized Phenothiazines, Eur. J. Med. Chem., 46: 3180-3188 (2011).
[23] Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E., The Protein Data Bank, Nucleic Acids Res., 28: 235−342 (2000).
[24] Morris G.M., Goodsell D.S., Halliday R.S., Huey R., Hart W.E., Belew R.K., Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function, J. Comp. Chem. 19: 1639-1662 (1998).
[25] Kitchen D.B., Decornez H., Furr J.R., Bajorath J., Docking and Scoring in Virtual Screening for Drug Discovery: Methods and Applications, Nat. Rev. Drug. Discov. 3: 935–949 (2004).[26] Accelrys., “Discovery Studio Visualizer Software” (2014).
[27] DeLano W.L., “The PyMOL Molecular Graphics Sstem”, DeLano Scientific LLC, San Carlos, CA, USA (2013).
[28] Tagg J. R, McGiven A. R., Assay system for bacteriocins, Appl. Microbiol., 21: 943-950 (1971).