Synthesis and Biological evaluation of Some Novel Hybrid Heterocyclic compounds

Abstract

Part 1 The cyclocondensation reaction of precursor 1-(1H-benzo[d]imidazol-2- yl)guanidine and the proper bis aldehydes via base-catalyzed cyclization methodology successfully yielded bis(benzo[4,5]imidazo[1,2 a][1,3,5]triazines) linked to phenoxymethyl moieties tethered aliphatic and aromatic spacers. In most cases, we were able to isolate the non-oxidized form, whereas in few cases we isolated the oxidized constitutions. The antibacterial activity was evaluated for these bis-compounds 5a-c, and 6d,e bearing aliphatic spacer, 10a,b bearing phenyl spacer, 12 bearing naphthyl spacer, in addition to 16 linked by phenoxy group using the serial dilution method to investigate the MIC (minimum inhibitory concentration) against different bacterial strains, where most of the compounds revealed a promising antibacterial effect against these strains, and our results were confirmed by molecular docking of these compounds with unique proteins. Part 2 A new series of bis(1,3,4a,9-tetraza-4H-fluoren-2-amine) derivatives (BTFAs) featuring aliphatic or piperazine linkers was successfully produced through a base- catalyzed cyclocondensation of 1-(1H benzo[d]imidazol-2-yl)guanidine with the corresponding bis-aldehydes. The compounds were evaluated against Gram-positive and Gram-negative bacterial strains. Of the synthesized derivatives, compound 14 exhibited the most potent antibacterial activity, showing a minimum inhibitory concentration (MIC) of 3.9 µg/mL and a remarkable selectivity index (SI = 70.5) against Enterococcus faecalis and Proteus vulgaris. Moreover, compound 7 showed strong enzyme inhibition with the lowest IC₅₀ value (7.95 ± 0.03 µg/mL) against MurE ligase, a crucial bacterial enzyme that plays a role in peptidoglycan biosynthesis. Molecular docking analyses indicated promising binding affinities (−6 to −10 kcal/mol) for various essential bacterial proteins