الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 297 |  |  |
| | | from | 297 | | |
Abstract
Incorporation of an adamantane functionality into candidate drug molecules modifies their physicochemical and pharmacological properties, due to the lipophilic nature of this moiety. The present study deals with design of new adamantane derivatives as potential antibacterial, antifungal and antiproliferative agents, based on reported activity of different drugs, drug-like and potentially active molecules incorporating this nucleus. The new compounds were intended to have adamantane conjugated with certain azoles of reported biological significance, such as thiazole, 1,2,4-triazole and tetrazole, based on the molecular hybridization concept of drug design. Other related derivatives were also considered. Results of antimicrobial evaluation against three strains of Gram-positive bacteria, two strains of Gram-negative and two strains of pathogenic fungi demonstrated that compound 87c, with 4-bromophenyl moiety at C4 of thiazole ring, had the most potent activity against Staphylococcus aureus strains, while compound 87l, with lipophilic 2-naphthyl moiety at C4 of thiazole ring, displayed the highest activity against Bacillus subtilis strain. The morpholino N-Mannich base of adamantane-triazole structure 94b, and methoxyphenylpiperazine N-Mannich base of adamantane-tetrazole structure 104b, with their HBA oxygen functionalities, exhibited strong activity against Gram-negative bacteria Escherichia coli. The S-alkylated carbimidothioates containing adamantane, especially 111b, 112b displayed strong activity against Escherichia coli Results of antiproliferative evaluation displayed the highest activity of the adamantane-thiazole hybrid 87k, with its methoxyphenyl group, against all tested cell lines, especially MCF-7. Compounds 94c, 97 and 104c appeared the most active N-Mannich bases of triazole and tetrazole sets of compounds. Unfortunately, None of the S-alkylated N-adamantanyl-S-alkylated carbimidothioate compounds 107-113 displayed significant activity against any of the tested cell lines. Molecular docking of the most active antiproliferative compounds was done against different targets (like SIRT1 enzyme, SHP2 enzyme, DHFR enzyme, ERα receptor and/or human 20S proteasome enzymes), by using AutoDock Vina, Schrödinger suite and MOE programs. In the molecular dynamic simulation, the six-membered rings of adamantane cage exhibited in chair conformation.