Chapter 3. The synthesis, antimicrobial and antidiabetic activity of benzimidazole scaffolds
3.3 Applications of benzimidazole derivatives as antimicrobial and antidiabetic agents
Scheme 3-14 Synthesis of Benzimidazo-isoindol-ones (195)
3.2.7 Benzimidazol-2-benzenesulphonamides synthesized form o-phenylenediamine and saccharin
The reaction of o-phenylenediamine and benzene sulphonamide (saccharin) produced 2-(1H- benzo[d]imidazol-2-yl)benzenesulfonamide (196) (Ashraf et al., 2016), probably by the lone pair of the amino group attacking the carbonyl group of saccharin, hydrolysing the amide bond.
The second amino group of o-phenylenediamine then reacts with the newly formed amide bond, forming the benzimidazol-2-benzene sulphonamide (196) after a dehydration step (Scheme 3-15).
3.3 Applications of benzimidazole derivatives as antimicrobial and antidiabetic agents
2016). The benzimidazole scaffold can be functionalised at a variety of positions, however the most common positions found to be derivatised are N-1, C-2, C-5 and C-6.
Scheme 3-15 Synthesis and mechanism of benzimidazol-2-benzenesulphonamides (196)
This short review focus on the antimicrobial and antidiabetic activities of benzimidazole derivatives since these two biological assays were carried out in this thesis.
3.3.1 Antimicrobial activity
Outlined below is a summary of benzimidazole structures with reported MIC values of <10 µg mL-1 and >30 mm zones of inhibition against one or more bacterial and fungal strains (Table 3-1 to Table 3-6). Essentially, these benzimidazoles were substituted at C-2 and N-1.
Compounds 197-199 contains substitution on N-1 only, with C-2 left unsubstituted. These substituents were propanoate esters. The benzene ring in these compounds were either unsubstituted (199), contained methyl groups at C-5 and C-6 (197) or a chloro group at C-6 (198) (Figure 3-3). Compounds 197 and 198 showed strain specific activity to Bacillus.
proteus and 199 showed activity against Staphyllococcus aureus, all having MIC values of 8 µg mL-1 (Wen et al., 2016).
Figure 3-3 Biologically active N-1 substituted benzimidazoles
Benzimidazoles 200-204 contain hydroxy, methyl, amino and nitro groups on the phenyl ring substituted at C-2 and bromo, nitro and methyl groups on the benzene ring of benzimidazole (Al-Ebaisat et al., 2015; Govindaraj et al., 2016). Compounds 205 and 206 contain a 2- benzamide group at C-2, with the benzene ring of the benzimidazole being unsubstituted in 205 and substituted with a bromo group at C-6 in 206 (Govindaraj et al., 2016; Reddy et al., 2016). Compound 207 also contained a phenyl group at C-2, but with a phenyl tetrazolo moiety attached at the ortho position (Reddy et al., 2016). Compound 208 contains a fluoro group at C-5 and a methyl-5-fluorouracil moiety at C-2, while compounds 209-214 contains a thio-6- methyl pyrimidine moiety with fluoro, chloro, bromo, methyl, methoxy and trifluoromethyl groups (209-214) (Chen et al., 2014; Fang et al., 2016). Compounds 215-216 contains a phenyl substituted thiourea moiety at C-2, with trifluoromethyl groups on the phenyl ring and propyl and butyl groups substituted at the nitrogen of the thiourea group (Figure 3-4) (Madabhushi et al., 2014). Compounds 208 and 210 showed excellent MIC values of 2 µg mL-1 against the fungal strain (Candida albicans) and Gram –ve strain (Stenotrophomonas maltophilia).
Benzimidazoles 217-327 all contained an imidazo-thiadiazol group attached to C-2 through C- 5' of the imidazole ring in the substitutent. These substitutents further contained fluoro, chloro
and methoxy groups on the phenyl ring at C-4' of the imidazole group (Ramprasad et al., 2015).
Compounds 238-249 contained thiomethyl-1,2,3-triazol-1-ylarylethylideneaceto-hydrazide groups at C-2, where the phenyl group was substituted with halogens, hydroxy, methoxy, isopropyl or dimethylamino groups (Youssif et al., 2014).
Figure 3-4 Biologically active C-2 substituted simple benzimidazoles
Compounds 250-267 each contained fluoroquinolones attached to C-2 through a piperidine linker, either directly (250 and 251) or through a methylene (252-261), ethylene (262-263), ethylamine (264-265) or imine group (266-267) (Zhang et al., 2016). The nitrogen of the fluoroquinoline moiety was substituted either with an ethyl group or with a cyclopropyl group and the benzene ring of the benzimidazole moiety was either unsubstituted or contained halogens (Br, Cl and F) or a nitro group. In addition, compound 268 contained an ethylidene- pyridine-6-arylimino-3,5-dicarbonitrile-4-nitrophenyl group at C-2 (Figure 3-5 and Figure 3-6) (Desai et al., 2014). Among these, compounds 257 and 259 showed the best antimicrobial activity with MIC values ranging from 0.125-1 µg mL-1 against Gram +ve and –ve bacterial strains. The other compounds also showed good MIC values of between 0.5-10 µg mL-1.
The next class of benzimidazoles contain substitution at both N-1 and C-2. Compounds 269- 272 contain ethyl, propyl, butyl and 3-F-benzyl groups at N-1, while C-2 is attached to a substituted 5-fluorouracil moiety (Fang et al., 2016).
Figure 3-5 Biologically active C-2 substituted complex benzimidazoles
Figure 3-6 Biologically active C-2 substituted complex benzimidazoles
Compounds 273-274 contains a 2,4-difluorobenzyl group at N-1 and a 3,5-ditrifluoromethyl methylaminophenyl group at C-2 (Huizhen et al., 2014). In addition, 275 and 276 has a N-
al., 2016). Compounds 277-301 all contain a piperidine linked fluoroquinolone linked to C-2 similar to 250-267, but now with either an ethyl group or a substituted benzyl group at N-1 (Figure 3-7) (Zhang et al., 2016). Of these, compounds 292, 295 and 299 showed the best activity against Gram +ve and Gram –ve bacterial strains and fungal strains with MIC values ranging from 0.03-8 µg mL-1. Other compounds also showed good antimicrobial activity against certain bacteria.
Figure 3-7 Biologically active N-1 and C-2 substituted complex benzimidazoles
Compounds 302-316 were slightly different to all the other compounds discussed previously.
Compounds 302-304 contained an imine at C-2 and either phenylpropyl or 2-oxo-2- phenylethyl groups at N-1 and N-3 (Mavrova et al., 2015). Compounds 305-316 contain a propyl chain at N-1, a 2,4-dichlorophenyl moiety at C-2 and substituted benzilidene hydrazones
against the fungal strain, Aspergillus niger with MIC values of 3.12-6.25 µg mL-1. Compound 315 showed broad spectrum antimicrobial activity with MIC values of 3.12 to 6.25 µg mL-1.
Figure 3-8 Biologically active N-1, N-3 and C-2 substituted complex benzimidazoles 3.3.2 Antidiabetic activity
Two types of benzimidazoles showed α-glucosidase inhibition with reported IC50 values of
<25 µg mL-1 (Table 3-7). This includes benzimidazole 318 with a 4-cyanophenyl moiety at C-2 and a 4-cyanobenzyl moiety at N-1 and compounds 319-333 with methyl groups at C-5 and C-6 and a substituted benzohydrazide group at C-2 containing hydroxy, methoxy, chloro, and methyl groups. The most active of these compounds were 319, 321, 324-325 and 333 with IC50 values of <9 µg mL-1 (Figure 3-9; Table 3-7) (Dinparast et al., 2016; Khairunissa et al., 2016). In addition, 2,3-dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole (317) (Figure 3-9) coupled to hydroxyethyl starch (HES) resulted in a 67% reduction in blood glucose levels of rats (Abbas et al., 2015).
Table 3-1 Antimicrobial activity of benzimidazole compounds (197-216)
Comp.
No.
Gram +ve Gram -ve Fungi
M.
luteus
S.
aureus
B.
proteus
E.
coli
P.
aeruginosa
S.
maltophilia
C.
albicans
S.
cerevisiae
C.
glabrata
C.
krusei
MIC MIC DD MIC DD MIC
197 - - - 8 - - - -
198 - - - 8 - - - -
199 - 8 - - - -
200 - - - 6.25 6.25
201 - - - 6.25
202 - - - 6.25
203 - - - 6.25
204 - - - - 30 - - - -
205 - - - - 30 - - - -
206 - - 32 - 36 - - - -
207 - - 32 - 36 - - - -
208 - 8 - - - 2 8 -
209 - - - 8 - - -
210 - 8 - - - - 2 - - - -
211 - - - 4 8 - - -
212 - - - 8 - - - -
213 - - - 8 - - - -
214 - - - 8 - - - -
215 - - - 6.25 - - - - -
216 6.25 - - - -
MIC = Minimum inhibitory concentration in µg mL-1; DD = Disc diffusion method, zone of inhibition in mm
M. luteus = Micrococcus luteus; E. coli = Escherichia coli; P. aeruginosa = Pseudomonas aerugoinosa; S. cerevisiae = Saccharomyces cerevisiae; C. glabrata = Candida glabrata; C. krusei = Candida krusei.
Table 3-2 Antimicrobial activity of benzimidazole compounds (217-238)
Comp.
No.
Gram
+ve Gram -ve Fungi
S.
aureus E.
coli
P.
aeruginosa S.
typhi
A.flavus C.albicans C.
Keratinophilum MIC (µg mL-1)
217 6 4 7 3 3 3 4
218 4 5 4 5 5 4 5
219 3 4 4 3 3 4 3
220 4 4 5 6 3 3 4
221 - - - - 6 6 5
222 4 4 3 4 5 5 4
223 3 3 2 3 - - -
224 7 5 8 3 4 3 4
225 5 5 6 4 5 5 4
226 4 5 2 3 4 5 4
227 3 4 6 4 - 6 -
228 5 4 3 - 5 2 3
229 - - - - 2 2 3
230 2 4 3 2 3 - 4
231 3 4 1 2 - 9 -
232 9 - - 10 7 6 8
233 4 4 5 3 6 - 7
234 9 6 8 6 - 4 -
235 3 4 4 4 3 - 5
236 5 5 3 6 - 4 -
237 - 8 9 8 3 - 2
238 - - - 6.25* -
MIC = Minimum inhibitory concentration in µg mL-1; *= MIC in µM