Novel Benzo[d]imidazole-based Heterocycles as Broad Spectrum Anti-viral Agents: Design, Synthesis and Exploration of Molecular Basis of Action.

The design and synthesis of a novel series of benzo[d]imidazole-based heterocycles and their biological evaluation as antiviral agents are reported herein. 1-(1-Methyl-1H-benzo[d]imidazol- 2-yl)-2-thiocyanatoethanone 2 was used as a key intermediate for the synthesis of the thiazolylhydrazine 4, the thiazolylamine 5 and the methylthiazole 7. Coupling of compounds 5 or 7 with the appropriate diazotized aromatic amines gave the diazenyl derivatives 6a-c and 8a-c, respectively. The quinazoline derivative 12 was also synthesized. On the other hand, the phenylthio 20 and the phenylsulphonyl 22 bioisosteresand their respective diazenyl derivatives 21a-c and 23a-c were prepared. The synthesized compounds were evaluated for their HIV-1, HCV, SSPE and H1N1 inhibitory activities and were found to display very promising results. Furthermore, to investigate the underlying possible mechanism of action, in vitro and in silico screening of this series of benzo[d]imidazoles was performed against the viral enzymes HIV-1 RT, HCV NS3/4A serine protease and H1N1 NA1. Overall findings of the executed investigations highlight these novel compounds as very promising potent, broad spectrum antiviral agents.

Synthesis of new N-phenylpyrazole derivatives with potent antimicrobial activity.

The versatile synthons 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2) were used as precursors for the synthesis of a series of phenylpyrazoles with different aromatic ring systems at position 4. The antimicrobiological evaluation of the newly synthesized compounds was carried out in vitro assays for antifungal and antibacterial activities. Amongst the tested compounds, 4-acetyl-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (1), 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2), 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-(2-aminothiazol-4-yl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (17) showed interesting antimicrobial properties. In particular, all tested compounds produced inhibitory effects against pathogenic yeast (Candida albicans) similar or superior to those of reference drug. In addition, compound 3 showed excellent activity against pathogenic mould (Aspergillus). From structure-activity relationship (SAR) point of view, the attachment of bromoacetyl moiety to pyrazole ring can be considered as a breakthrough in developing a new therapeutic antifungal agent related to phenylpyrazole system.

Synthesis of new 3-pyridinecarboxylates of potential vasodilation properties.

2-(alicyclic-amino)-4,6-diaryl-3-pyridinecarboxylates 5a-d were prepared via aromatic nucleophilic substitution reaction of secondary amines (piperidine or morpholine) with 2-bromo-3-pyridinecarboxylate derivatives 3a,b. The latters were obtained through bromination of 3-aryl-4-benzoyl-2-cyanobutyrates 2a and 2b, which were obtained from the base promoted addition of ethyl cyanoacetate to 2-propen-1-ones 1a and 1b, with bromine in glacial acetic acid. Reaction of 3 with piperazine hexahydrate in 2:1 molar ratio afforded 1,4-bis[(ethyl 4,6-diaryl-3-pyridinecarboxylate)-2-yl]piperazines 6a,b. Reaction of 3 with anilines in refluxing pyridine unexpectedly gave 2-(aryl-amino)-3-pyridinecarboxylates 8a-g and 2-amino-3-pyridinecarboxylates 9a and 9b. Vasodilation activity screening for the synthesized pyridinecarboxylates using isolated thoracic aortic rings' standard method of rats shows considerable properties. Compounds 5b, 5c, 6b and 8g reveal remarkable vasodilation potency (IC50, concentrations necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) 0.175, 0.146, 0.229 and 0.233 mM, respectively.