Synthesis and in silico investigation of Schiff base derivatives of 1H-indole-2,3-diones and their Co(II) and Ni(II) complexes as antimicrobial agents

Helen O. Echekwube , Pius O. Ukoha , Oguejiofo T. Ujam , Charles O. Nwuche , Jonnie N. Asegbeloyin and Akachukwu Ibezim

Abstract
3-[(2-aminophenyl)imino]-1,3-dihydro-2H-indol-2-one, (Lo), 1,3-phenylenediazanylylidene di (1,3-dihydro-2H-indol-2-one), (Lm) and 1,4-phenylenediazanylylidene di(1,3-dihydro-2H-indol-2-one) (Lp) were synthesized by the reaction of 1H-indole-2,3-dione with benzene-1,2-diamine, benzene-1,3-diamine and benzene-1,4-diamine, respectively. The reaction of Lo, Lm and Lp with Co(II) and Ni(II) halides gave the corresponding coordination complexes which were characterized by elemental analysis, molar conductance, infra-red, GC-MS and electronic spectral studies. Docking of the 1H-indole-2,3-diones toward the binding sites of penicillin binding protein and DNA gyrase showed they interacted favourably with the test antibacterial targets at ∆Gs range of -2.51 to -5.48 kcal/mol. In accordance to literature report, coordination of cobalt and nickel to the ligands yielded metal complexes which exhibited improved interaction with the protein targets (at ∆Gs range of -8.70 to -10.20 kcal/mol). In vitro antimicrobial studies against some microorganisms showed that some of the compounds were active against few Gram negative and Gram positive bacteria. The Lo, Lm and Lp had no activity against any of the test microorganisms but the Co(II) and Ni(II) complexes, showed antibacterial activity. The [Co(Lo)₂] and [Ni(Lo)₂] complexes generated the least antibacterial response. [Co(Lo)₂] was ineffective against E. coli 6 and Staphylococcus sciuri subsp sciuri while Bacillus subtilis was resistant to [Ni(Lo)₂] which moderately inhibited E. coli 14 (7 mm). Both compounds indicated zero activity against Pseudomonas aeruginosa. The complex that evoked the highest bactericidal activity were [CoLm]Cl₂ and [NiLp]Cl₂. The antibiogram activity of [CoLm]Cl₂ was found between 20 and 30 mm with E. coli 6 displaying greater sensitivity (30 mm) and S. sciuri the least (20 mm). The activity of [NiLp]Cl₂ complex indicate that the activity spectrum of the organisms occurred within 29 and 45 mm range; the least sensitive were E. coli 14 (29 mm) and B. subtilis (29 mm) while the most sensitive was S. sciuri subsp sciuri (45 mm). The two compounds were further studied for minimum inhibitory concentration (MIC) and their binding modes towards the studied protein targets were analyzed. Result indicate that the MIC of 1.25 µg/mL was determined for the complex ([NiLp]Cl₂) against S. sciuri subsp sciuri (12 mm) while in case of [CoLm]Cl₂, the MIC was 2.5 µg/mL (13 mm) against the same organism. The binding modes predicted for [CoLm]Cl₂ and [NiLp]Cl₂ identified essential residues necessary for interaction with the studied proteins and which could be targeted during structural/activity optimization.

Keywords
1H-Indole-2,3-dione; Anti-microbial activity; Physicochemical properties; Docking; Binding mode.

DOI
10.21472/bjbs.061207

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References
A-Hasani, R. A. M.; Mohammed, S. M.; Rasheed, E. M. Synthesis, characterization and biological study of Cr(III), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes with a new tetradentate Schiff base ligand. Iraqi National Journal of Chemistry, v. 43, p. 392-398, 2011.

Abdul-Manam, M. A. F.; Cordes, D. B.; Slawin, A. M. Z.; Buhl, M.; Liao, V. W. Y.; Chua, H. C.; Chebib, M.; O'Hagen, D. The synthesis and evaluation of fluoro-, trifluoromethyl and iodomuscimols as GABA agonists. Chemistry, v. 23, p. 10848-10852, 2017.

Agbo, J. N.; Ukoha, P. O. Synthesis, characterization and preliminary antimicrobial activities of some azo ligands derived from aminoantipyrine and their Co(II), Fe(III), and Os (VIII) complexes. International Journal Chemistry, v. 20, p. 217-225, 2010.

Akpanisi, L. E. S. Organic spectroscopy. Nigeria: Loius Chumez Printing Enterprises, 2004.

Aungst, B. J. Optimizing oral bioavailability in drug discovery: An overview of design and testing strategies and formulation options. Journal of Pharmaceutical Sciences, v. 106, p. 921-929, 2017.

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 Research, v. 28, p. 235-342, 2000.

Bhrigu, B.; Pathak, D.; Siddiqui, N.; Alam, S. M.; Ahsam, W. Biological activity of indoline derivatives. International Journal of Pharmacy Sciences and Drug Research, v. 2, p. 229-234, 2010.

Bollenbach, T. Antimicrobial interaction: Mechanisms and implications for drug discovery and resistance evolution. Current Opinion in Microbiology, v. 27, p. 1-9, 2015.

Breitmaier, E.; Voelter, W. Carbon-13 NMR spectroscopy. 3. ed. Weinheim: VCH, 1987.

Cerchiaro, G.; Ferreira, A. M. D. Oxindoles and copper complexes with oxindole: Derivatives as potential pharmacological agents. Journal of the Brazilian Chemical Society, v. 17, p. 1473-1485, 2006.

CCG - Chemical Computing Group. Molecular Operating Environment (MOE). Software Edition, 2010.

Chinnasamy, R. P.; Sundararajan, R.; Govindaraja, S. Synthesis, characterization and analgesic activity of novel Schiff base of isatin derivatives. Journal of Advanced Pharmaceutical Technology & Research, v. 1, p. 342-347, 2010.

Dunn, M. T.; McClure, D. S.; Pearson, B. C. Some aspects of Crystal Field Theory. New York: Harper and Row Publishers, 1965.

Halgren, T. A. Merck molecular force field. Journal of Computational Chemistry, v. 17, p. 490-641, 1996.

Hassan, A. M. Co(II) and Fe(II) Schiff base chelates derived from isatin and some amino acids. Medical Journal of Islamic World Academy of Sciences, v. 4, p. 271-294, 1991.

Housecroft, C. E.; Sharpe, A. G. Inorganic Chemistry. 3. ed. London: Pearson Education England, 2008.

Ibezim, A.; Nwodo, N. J.; Nnaji, N. J. N.; Ujam, O. T.; Olubiyi, O. O.; Mba, C. J. In-silico investigation of morpholines as novel class of trypanosomal triosephosphate isomerase inhibitors. Medicinal Chemistry Research, v. 26, p. 180-189, 2016.

Ibezim, A.; Debnath, B.; Ntie-Kang, F.; Mbah, C. J.; Nwodo, N. J. Binding of anti-trypanosome natural products from African flora against selected drug targets: A docking study. Medicinal Chemistry Research, v. 26, p. 562-579, 2017.

Ibezim, A.; Olujide, O. O.; Ata, K.; Mbah, C. J.; Nwodo, N. J. Structure based study of natural products with anti-schistosoma activity. Current Computer-Aided Drug Design, v. 13, p. 91-100, 2017.

Ibezim, A.; Onyia, K.; Ntie-Kang, F.; Nwodo, J. N. Drug like properties of potential anti-cancer compounds from Cameroonian flora: A virtual studies. Journal of Applied Pharmaceutical Science, v. 5, p. 133-137, 2015.

Iman, S. A.; Varma, R. S. Isatin-3-anils as excystment and cysticidal agents against Schizopyrenes russelli. Experimentia, v. 31, p. 1287-1288, 1975.

Kazuma, N.; Shigeru, K.; Fujio, T.; Masaki, H.; Yoshio, I. Condensation of isatin with O-phenylenediamine. Bulletin of the Chemical Society of Japan, v. 55, p. 2293-2294, 1982.

Kriza, A.; Ignat, I.; Stanica, N.; Draghici, C. Synthesis and characterization of Cu(11), Co(11) and Ni(11) complexes with Schiff bases derived from isatin. Revista de Chimie, v. 62, p. 696-701, 2011.

Lee, J.D. Concise Inorganic Chemistry. 5. ed. New York: Black Well Science, 1998.

Manan, M. F.; Karimah, K.; Abdul-Manan, M. A. F. Synthesis, characterization and conductivity studies of Schiff base ligand derived from isatin and o-phenylenediamine with its Cobalt(II) metal complex and Lithium-Schiff base compound. The Malaysian Journal of Analytical Sciences, v. 16, p. 318-324, 2012.

Mashaly, M. M.; Abd-Elwahab, Z. H.; Faheim, A. Preparation, special characterization and antimicrobial activities of Schiff base complexes derived from 4-Aminoantipyridine mixed ligand complexes with 2-Aminopyridine, 8-Hydoxyquinoline and oxalic acid and their pyrolytical products. Journal of the Chinese Chemical Society, v. 51, p. 901-915, 2004.

Medvedev, A. E.; Clow, A.; Sandler, M.; Glover, V. Isatin: A link between natriuretic peptides and monoamines? Biochemical Pharmacology, v. 52, p. 385-391, 1996.

Mishra, A. P.; Mishra, R.; Jain, R.; Gupta, S. Synthesis of new Vo(II), Co(II), Ni(II) and Cu(II) complexes with isatin-3-Chloro-4-floroaniline and 2-Pyridinecarboxylidene-4-aminoantipyrine and their antimicrobial studies. Mycobiology, v. 40, p. 20-26, 2012.

Mohamed, G. G.; Omar, M. M.; Hindy, A. M. Metal complexes of Schiff bases: Preparation, characterization and biological activity. Turkish Journal of Chemistry, v. 30, p. 361-382, 2006.

Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a larmarekian genetic algorithm and emperical binding free energy function. Journal of Computational Chemistry, v. 19, p. 1639-1662, 1998.

Nagajothi A.; Kiruthika A.; Chitra S.; Parameswari, K. Synthesis and characterization of Tetradentate Co(II) Schiff base complexes: Antimicrobial and DNA cleavage studies. International Journal of Pharmacy and Biomedical Sciences, v. 3, p. 1768-1778, 2012.

NCCLS - National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: Approved standard m7-A3. 3. ed. Villanova, PA: NCCLS, 1993.

Ntie-Kang, F.; Nwodo, J. N.; Ibezim, A.; Simoben, C.V.; Karaman, B.; Ngwa, V.; Sippl, W.; Adikwu, M. U.; Mbaze, L. M. Molecular modeling of potential anticancer agents from African medicinal plants. Journal of Chemical Information and Modeling, v. 54, p. 2433-2450, 2014.

Nwuche, C. O.; Ujam, O. T.; Ibezim, A.; Ujam, I. B. Experimental and in-silico investigation of anti-microbial activity of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine, piperazine and morpholine. PLoS ONE, v. 12, e0170150, 2017.

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, v. 11, e0163467, 2016.

Pandeya, S. N.; Sriram, D. Synthesis and antimicrobial activity of Schiff's and Mannich bases of isatin and its derivatives. Acta Pharmaceutica Turcica, v. 40, p. 33-38, 1998.

Pandeya, S. N.; Sriram, D.; Nath, G.; Clercq, E. Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin and its derivatives with triazole. Arzeimittelforschung, v. 50, p. 55-59, 2000.

Pandeya, S. N.; Sriran, D.; Nath, G.; De Clercq, E. Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin Mannich bases. European Journal of Medicinal Chemistry, v. 35, p. 249-255, 2000.

Pandeya, S. N.; Yogeeswari, P.; Sriram, D.; De Clercq, E.; Pannecouque, C.; Witvrouw, M. Synthesis and screening for anti-HIV activity of some n-Mannich bases of isatin derivatives. Chemotherapy, v. 45, p. 192-196, 1999.

Raman, N.; Raja, J.; Sakthivel, A. Synthesis, spectral characterization of Schiff base transition metal complexes: DNA cleavage and antimicrobial activity studies. Journal of Chemical Sciences, v. 119, p. 303-310, 2007.

Reddy, R. K.; Suneetha, K.; Karigar, C. S.; Manjunth, N.; Mahendra, K. Cobalt(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), UO2(VI) and th(IV) complexes from ONNN Schiff base ligand. Journal of the Chilean Chemical Society, v. 53, p. 1653-1657, 2008.

Sarangapani, M.; Reddy V. M. Pharmacological screening of isatin-[N-(2-alkyl benzoxazole-5-carbonyl)]hydrazones. Indian Journal of Pharmaceutical Sciences, v. 59, p. 101-105, 1977.

Silva, J. F. M.; Garden, S. J.; Pinto, A. C. The chemistry of isatins: A review from 1975 to 1999. Journal of the Brazilian Chemical Society, v. 12, p. 273-324, 2001.

Singh, A. K. Inhibition of mild steel corrosion in hydrochloric acid solution by 3-(4-((Z)-indolin-3-ylideneamino) phenylimino) indolin-2-one. Industrial & Engineering Chemistry Research, v. 51 p. 3215-3223, 2012.

Singh, D. P.; Grover, V.; Kumar, K.; Jain, K. Metal ion prompted macrocyclic complexes derived from Indole-2,3-dione (isatin) and O-phenylenediamine with their spectroscopic and antibacterial studies. Acta Chimica Slovenica, v. 57, p. 775-780, 2010.

Singh, P.; Dandia, A.; Khandelwal, A. Facile chemoselective synthesis of novel 6-aryl-12H-indole (2, 3-e]{1,4}benzodiazocine derivatives by reaction of 3-aroylmethylene-2H-indol-2-ones with o-phenylenediamine. Indian Journal of Chemistry, v. 49, p. 1135-1139, 2010.

Tagg, J. R.; Mc-Given, A. R. Assay system for bacteriocins. Applied Microbiology, v. 21, p. 943, 1971.

Todeschini, A. R.; De Miranda, A. L. P.; Da Silva, K. C. M.; Parrini, S. C.; Barreiro, E. J. Synthesis and evaluation of analgestic, anti-inflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives. European Journal of Medicinal Chemistry, v. 33, p. 189-200, 1998.

Ukoha, P. O.; Alioke, C. U.; Obasi, V. L.; Chah, K. F. Synthesis, spectroscopic characterization and preliminary antimicrobial studies of Mn(II) and Cu(II) complexes of two thiolates; S, S1-(2, 6–Diaminopyridine-3,5-Diyl-dibenzene Carbothioate (DBCT) and S-Benzyl Benzene Carbothioate (BBCT). Journal of Chemistry, v. 8, p. 231-239, 2011.

Varma, R. S.; Nobles, W. L. Antiviral, antibacterial, and antifungal activities of isatin N-Mannich bases. Journal of Pharmaceutical Sciences, v. 64, p. 881-882, 1975.

Verma, R. S.; Khan, I. A. Occurrence of extra-ovarian ovules in sunflower plants (Helianthus annus L.) treated with chloroflurenol. Polish Journal of Pharmacology and Pharmacy, v. 29, p. 549-594, 1977.

Wu, H. L.; Gao, Y. C. Synthesis, crystal structure and characterization of zinc (II) complexes with the tripod ligand tris(2-benzimidazolylmethyl)amine and α,β-unsaturated carboxylates. Transition Metal Chemistry, v. 29, p. 175-179, 2004.