Design and Synthesis of Novel Benzimidazoles and Analogues of Potential Anthelmintic Activity

Transcription

1 Mansoura University Pharm. Organic. Chem. Dept. Design and Synthesis of ovel Benzimidazoles and Analogues of Potential Anthelmintic Activity Thesis Presented By Basem Awad Mansour Mohamed B. Pharm. Sci., Mansoura University 1996 A thesis submitted in partial fulfillment of The Master Degree of Pharmaceutical Sciences (Pharmaceutical Organic Chemistry) Prof. asan M. asan Eisa (PhD) Prof. of Pharm. Org. Chem. Mansoura University Supervisors Dr. Waleed A. Bayoumi (PhD) Lecturer of Pharm. Org. Chem. Mansoura University Prof. Serry A. A. El Bialy (PhD) Prof. of Pharm. Org. Chem. and Vice- Dean for Graduate Studies and esearch Mansoura University 2014

2 ABSTACT Considering several literature enlightening the anthelmintic nature of the benzimidazole ring and its derivatives, new series of benzimidazole derivatives hybridized with pharmacophoric moieties possessing anthelmintic activity were designed, synthesized and evaluated for their anthelmintic activity. In order to obtain the target compounds, the following synthetic routes were adopted and found to be successful: 1. Condensation of o-phenylenediamine with the appropriate carboxylic acid to afford 1-Benzimidazole derivatives 50a-c. (Scheme Ӏ) 50a-c 2. Preparation of 5-nitro-1benzimidazole derivatives 58a-c via direct nitration of the corresponding benzimidazoles 50a-c, respectively O 2 (method 1), or through direct condensation of 4-nitrobenzene-1, 2-58a-c diamine with the appropriate carboxylic acid (method 2). (Scheme Ӏ) I

3 3. eduction of compounds 58a-c via Pd-C catalyzed hydrogenation (method 2 1) or utilizing FeSO 4 in aqueous Cl (method 2), to afford the corresponding amino derivatives 51a- 51a-c c, respectively. (Scheme Ӏ) 4. Cyclization of the appropriate 5- aminobenzimidazole with bromine in acidic medium through oxidative halogenation to afford 7imidazo[4,5-f]benzothiazole-2-amine 53a,b derivatives 53a,b. (Scheme Ӏ) 5. Acylation of 53a with methyl chloroformate in presence of diisopropylethylamine using MeO O S C 2 C1 2 /TF as solvent mixture, to afford methyl--(7-imidazo[4, 5-54 f]benzothiazol-2-yl)carbamate 54. (Scheme ӀӀ) II

4 6. Synthesis of salicyloyl chloride derivatives 68a,b through reaction of 5-(un)substituted salicylic acids 77a,b with oxalyl chloride in C 2 Cl 2 in presence of catalytic amounts of DMF. (Scheme ӀӀ) COCl O 68a,b 7. Amidation of 2-amino-6- (un)substituted-7-imidazo[4,5-f]- benzothiazole 53a,b with (un)substituted salicyloyl chloride 68a,b in DMF and pyridine, to produce 5-(un)substituted-2-hydroxy- -(6-(un)substituted-7- imidazo [4,5,f]benzothiazol-2-yl)benzamide 55a,b. (Scheme ӀӀ) 55a,b 8. Condensation of 3,4-diaminobenzoic acid with formic and acetic acids to produce 2-(un)substituted-1- OOC benzimidazole-5-carboxylic acid derivatives 52a,b, respectively. 52a,b (Scheme ӀӀӀ) III

5 9. Synthesis of benzimidazolyl acid chloride derivatives 83a,b through addition of oxalyl chloride to a ClOC solution of 52a,b in anhydrous C 2 Cl 2 in presence of catalytic amounts of DMF. (Scheme ӀӀӀ) 83a,b 56a,b 10. Amidation of 4-bromo-3-fluoroaniline with the acid chloride derivatives 83a,b in dry DMF and pyridine to obtain -(4-bromo-3-fluorophenyl)-2- (un)substituted-1-benzimidazole-5- carboxamide derivatives 56a,b. (Scheme ӀӀӀ) 11. Palladium-catalyzed cross-coupling reaction of aryl bornic acid 92 and the appropriate aryl halides 93a-d through Suzuki-Miyaura reaction to afford 5- (4-substituted phenyl)thiophene-2- carbaldehydes 94a-d. (Scheme IV) 94a-d IV

6 12. Synthesis of 2-substitited benzimidazoles 57a-h through condensation of the appropriate aromatic aldehydes 94a-d bisulfite ' S addition product with the appropriate 57a-h o-phenylenediamine. (Scheme IV). The previous synthetic reactions required the preparation of the following unavailable starting compounds and intermediates guided with published literature: 1. 1-Benzimidazole 50a Methyl-1-benzimidazole 50b (Trifluoromethyl)-1-benzimidazole 50c itro-1-benzimidazole 58a Methyl-5-nitro-1-benzimidazole 58b itro-2-(trifluoromethyl)-1-benzimidazole 58c benzimidazole-5-Amine 51a Methyl -1-benzimidazole-5-amine 51b (Trifluoromethyl)-1-benzimidazole-5-amine 51c ydroxybenzoyl chloride 68a Fluoro-2-hydroxybenzoyl chloride 68b benzimidazole-5-carboxylic acid 52a Methyl-1-benzimidazole-5-carboxylic acid 52b. V

7 14. 1-Benzimidazole-5-carbonyl chloride 83a Methyl-1-benzimidazole-5-carbonyl chloride 83b (4-Isopropoxyphenyl)thiophene-2-carbaldehyde 94a (4-Methoxyphenyl)thiophene-2-carbaldehyde 94b (4-ydroxyphenyl)thiophene-2-carbaldehyde 94c (4-Fluorophenyl)thiophene-2-carbaldehyde 94d. The formation and the purity of the newly synthesized compounds were checked by TLC and elemental analysis, whereas, structure elucidation was achieved through microanalytical and spectral data. Six of the newly synthesized compounds have been subjected to in vitro cercarial assay in order to screen their anthelmintic activity. Determination of the degree of survival index of the cercariae was carried. The results of biological screening revealed that, all the tested compounds showed significant anthelmintic activity. Among the tested compounds, compound 57h showed the best anthelmintic activity. Whereas compounds: 57c, 57d, 57g, 57a and 57b showed strong anthelmintic activity. VI