Synthesis and Structure Insights of Two Novel Broad-Spectrum Antibacterial Candidates Based on (E)-N′-[(Heteroaryl)methylene]adamantane-1-carbohydrazides

Abstract

Two new N′-heteroarylidene-1-carbohydrazide derivatives, namely; E-N′-[(pyridine-3-yl)methylidene]adamantane-1-carbohydrazide (1) and E-N′-[(5-nitrothiophen-2-yl)methylidene]adamantane-1-carbohydrazide (2), were produced via condensation of adamantane-1-carbohydrazide with the appropriate heterocyclic aldehyde. Both compounds were chemically and structurally characterized by 1H-NMR, 13C-NMR, infrared and UV-vis spectroscopies, and single crystal X-ray diffraction. The study was complemented with density functional theory calculations (DFT). The results show an asymmetrical charge distribution in both compounds, with the electron density accumulated around the nitrogen and oxygen atoms, leaving the positive charge surrounding the N-H and C-H bonds in the hydrazine group. Consequently, the molecules stack in an antiparallel fashion in the crystalline state, although the contribution of the polar contacts to the stability of the lattice is different for 1 (18%) and 2 (42%). This difference affects the density and symmetry of their crystal structures. Both molecules show intense UV-Vis light absorption in the range 200–350 nm (1) and 200–500 nm (2), brought about by π → π* electronic transitions. The electron density difference maps (EDDM) revealed that during light absorption, the electron density flows within the π-delocalized system, among the pyridyl/thiophene ring, the nitro group, and the N′-methyleneacetohydrazide moiety. Interestingly, compounds 1 and 2 constitute broad-spectrum antibacterial candidates, displaying potent antibacterial activity with minimal inhibitory concentration (MIC) values around 0.5–2.0 μg/mL. They also show weak or moderate antifungal activity against the yeast-like pathogenic fungus Candida albicans.

Thiophene‐containing compounds with antimicrobial activity

“…[ 188 ] As another example, hydrazone 210 (Figure 23) had broad‐spectrum antibacterial activity against Gram‐positive bacteria, but its antifungal activity was weak. [ 189 ] Hydrazone 211 (Figure 23) derived from a sulfonylhydrazine had poor antibacterial activity in an agar well diffusion test at 400 μg/well, but its anti‐ Candida activity was somewhat better (diameter of inhibition zone was 35% of that recorded for oxiconazole). [ 190 ] Despite being the most potent compound among its analogs with MICs as low as 125 μg/ml against several bacterial strains, hydrazone 212 (Figure 23) derived from another sulfonylhydrazine was nonetheless a very weak antibacterial agent compared to standard antibacterial drugs (e.g., tetracycline had MICs ranging from 0.025 to 0.625 μg/ml).…”

Synthesis, structural and in vitro biological evaluation of diamondoid-decorated lipophilic organotin(IV) derivatives

“…The anti-bacterial activity of organotin derivatives, including organotin carboxylates, is already welldocumented [33] so it seemed a natural step forward to evaluate the anti-bacterial potential of a variety of organotin species coupled with adamantane carboxylates. Further, broadspectrum anti-bacterial behaviour exhibited by adamantane-1-carbohydrazides in contrast to limited anti-fungal activity was ascribed to the lipophilic attributes of the molecules [81].…”

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction

“…According to experimental and molecular docking studies for the identification of chemical features of 11β-HSD1 inhibitors, a combination of an adamantane cage-and 1,2,4-triazole or other azole moieties could result in potent 11β-HSD1 inhibitors [15,16,[24][25][26][27][28][29]. In continuation with ongoing interest in the structural properties [30][31][32][33][34][35] and biological applications of adamantane-based derivatives [35][36][37][38][39], we report herein on the molecular structure insights, Hirshfeld surface analysis and pairwise interaction energies of three adamantane-linked 1,2,4-triazole N-Mannich bases, namely ethyl 4-[(3adamantan-1-yl)-4-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazine-1carboxylate (1), 5-(adamantan-1-yl)-4-ethyl-2-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2) and 5-(adamantan-1-yl)-4-allyl-2-[(4-(pyridin-2yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (3), which were proven to possess marked hypoglycemic activity [39]. Molecular docking analyses at the 11β-HSD1 active site were also performed, in order to predict the potential 11β-HSD1 binding affinity and binding interactions of the compounds.…”