SYNTHESIS & BIOLOGICAL EVALUATION OF SCHIFF BASES OF BENZIMIDAZOLE DERIVATIVES

1. SYNTHESIS & BIOLOGICAL EVALUATION OF SCHIFF BASES OF BENZIMIDAZOLE DERIVATIVES Dr Gopal Natesan Department o f Medicinal Chemistry Faculty of Pharmacy MAHSA University, Kuala Lumpur

2. INTRODUCTION Bacteria Adaptation & evolution Bacterial Infection TREATMENT Resistant strain Antibiotic/ Antibacterial agents

4. Multidrug-resistance organism (MDRO) • Bacteria develop resistance towards more than one class of antibiotics Methicillin-Resistant Staphylococcus aureus (MRSA) • Treatment effectiveness • Prolonged treatment duration

5. Selected Pharmacophore Benzimidazole Heterocyclic compounds (Source: Gaba, 2013 )

6. Problems Associated with existing drugs Usage of chemotherapeutic agents for infectious diseases treatment are LIMITED: Resistance strain, Toxicities, Adverse effects NEED : Newer chemical entities with better efficacy. BENZIMIDAZOLEpharmacophore: alternate for the problems associated with existing treatment.

7. Aim & Objectives To design, synthesise & study the antibacterial property of novel 1-[(1H-benzo[d]imidazol-1-yl) (4-substituted phenyl) methylene]-2- (mono/di/tri-substituted methoxybenzylidene) hydrazine derivatives.

8. Literature Review

9. Benzimidazole possess potential antibacterial activity. • Novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles.(Source: Kumar et al 2006)

10. 1,2-substitutionenhance the inhibitory activity Activity: Aromatic amidine substituent > Aliphatic amidine or amide substituent

11. electron withdrawing group in the aromatic ring did not exhibit antibacterial activity • Schiff base and • inhibitory activity • chloro, bromo or methyl substituent on the hydrazone aromatic ring increases the activity • Hydrazone moiety bearing benzimidazole derivatives(Source: Ozkay et al. 2010)

12. Scheme for synthesis of title compound

13. Antibacterial activity Evaluation (Agar well diffusion method) Preparation of agar with bacterial suspension (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Escherichia coli ) Three wells DMSO (Negative control) Tested compounds (100 µg/ml) Norfloxacin (Positive control) Diffusion at room temperature for 2 hours Incubation of agar plates at 37ºC±10ºC for 24 hours Results: Inhibition zone

14. RESULT & DISCUSSION (Mechanims involved in Step 1 & 2) STEP 1: Philips condensation STEP 1: Nucleophilic addition mechanism (Schottenbaumann reaction) Nucleophilic attack - reformation of the carbon-oxygen double bond and a chloride ion are pushed off - removal of a hydrogen ion from the nitrogen - react with chloride ion, and released as HCl

15. Mechanism involved in Step 3 STEP 3: Primary undergo nucleophilic addition with ketones moiety to give carbinolamines intermediate which then dehydrate to give substituted imines

16. (Mechanism involved in Step 4) STEP 4: Nucleophilic addition followed by dehydration forms benzylidenecpd

17. RESULT & DISCUSSION ( Synthetic method- Step 1)

18. RESULT & DISCUSSION ( Synthetic method- Step 2) 7.65 : N-H (Step 1)

19. RESULT & DISCUSSION ( Synthetic method- Step 3)

20. RESULT & DISCUSSION ( Synthetic method- Step 4)

21. Physical data of synthesis of 1-[(1H-benzo[d]imidazol-1-yl) (4’-substituted phenyl) methylene]-2-(mono/di/tri-substituted methoxybenzylidene) hydrazine derivatives (IVa-IVh)

22. RESULT & DISCUSSION Antibacterial activity Note: - = no activity; + = poor activity (1-5 mm); ++ = moderate activity (6-10 mm); +++ = good activity (11-15 mm); ++++ = excellent activity (16-20mm)

23. CONCLUSION • 10 Novel benzimidazole derivatives were synthesised successfully and in good yield. • All the newly synthesised compound’s structure was established on the basis of NMR and Mass Spectroscopy and the structure assigned on them are satisfactory. • All the test compounds exhibited mild to moderate antibacterial activities only. • Compounds (IVb) and (IVe) showed better antibacterial activity compared to other test compounds with additional poor activity against gram negative bacteria.

24. FUTURE SCOPE OF STUDY • To explore other pharmacological properties of the synthesised compound. • Synthesise more number of different analogs to study the SAR of the prosposed compounds . • Evaluation of antimicrobial properties in higher doses and also in different organisms. • Study of the molecular mechanism of action of these synthesised compounds.

25. REFERENCES • Ansari, K.F., and Lal, C. 2009, Synthesis, physicochemical properties and antimicrobial activity of some new benzimidazole derivatives, European Journal of Medicinal Chemistry. 44: 4028-4033. • Ansari, K.F., and Lal, C. 2009, Synthesis and evaluation of some new benzimidazole derivatives as potential antimicrobial agents, European Journal of Medicinal Chemistry. 44: 2294-2299. • Goker, H., Ozden, S., Yildiz, S., and Boykin, D.W. 2005, Synthesis and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines, European Journal of Medicinal Chemistry. 40: 1062-1069. • Karatas, H., Alp, M., Yildiz, S., and Goker, H. 2012, Synthesis and Potent In-vitro activity of novel 1H-Benzimidazoles as anti-MRSA agents, Chemical Biology &Drug Design. 80: 237-244. • Kumar, B. V. S., Vaidya, S.D., Kumar, R. V., Bhirud, S. B., and Mane, R. B. 2006, Synthesis and anti-bacterial activity of some novel 2-(6-flurochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazole, European Journal of Medicinal Chemistry. 41: 599-604. • Ozkay, Y., Tunali, Y., Karaca, H., Isikdag, I. 2010, Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazone moiety, European Journal of Medicinal Chemistry. 45: 3293-3298. • Sharma, S., Gangal, S. and Rauf, A. 2009, Convenient one-pot synthesis of novel 2-substituted benzimidazoles, tetrahydrobenzimidazoles and imidazoles and evaluation of their in vitro antibacterial and antifungal activities, European Journal of Medicinal Chemistry. 44: 1751-1757.

26. NDD Team Mr Saravanan, Ms. ChooShuet Yee, Ms. Lim Pei Cheng and Ms. Jecintha THANK YOU…