Antispasmodic and antimicrobial activities of pyrazole‐containing ferrocenyl alkanols versus their phenyl analogs, and the entry point to potential multitarget treatment for inflammatory bowel diseases

Abstract

Inflammatory bowel diseases (IBM), such as Crohn's disease, and their common complications represent a global health challenge. Many pyrazole derivatives, such as the spasmolytic drug metamizole, have already found their place among the frequently used therapeutic agents. Alteration of the structure of established therapeutic drugs by introducing a ferrocene moiety was shown to be a promising way for the discovery of new drugs. Herein, two libraries of analogous ferrocenyl (1a‐1j) and phenyl alkanols (2a‐2j) containing a pyrazole core, among which 17 completely new structures, have been synthesized, and structurally and electrochemically characterized. These compounds, along with the aldehydes used for their synthesis, were tested in parallel for their antispasmodic, acetylcholinesterase‐inhibitory, and antimicrobial activities to evaluate their potential as multitarget IBM drugs. The antispasmodic activity was investigated by assessing their effect on both the amplitude and number of spontaneous contractions of isolated rat ileum. Their antimicrobial effect was evaluated against a panel of Gram‐positive and Gram‐negative bacterial strains and fungi. It was found that several of the evaluated compounds displayed gastrointestinal smooth muscle relaxant activity, among them, 1‐(1H‐3‐ferrocenyl‐1‐phenylpyrazol‐4‐yl)‐3‐methylbutan‐1‐ol (1d) showed a remarkable effect by superseding the activity of papaverine. Together with the fact that it represents one of the most antimicrobially active investigated compounds, 1d is a good candidate for further pharmacological evaluation as a multitarget drug for IBM.

New Iron Twist to Chloroquine─Upgrading Antimalarials with Immunomodulatory and Antimicrobial Features

“…The observed shifts were attributed to the deshielding effect caused by an intramolecular H-bond between the Ar-NH and the alkyl N, and these derivatives exhibited higher antiplasmodial activity. It was also noted that this effect depended on the distance between the nitrogens, and usually diminished in analogues with longer alkyl linkers, possibly as the distance that separates these two nitrogens does not allow efficient H-bonding or owing to some conformational restrictions . These results were in agreement with the findings that the improved action of FQ is due to the presence of analogous intramolecular bonding, stabilizing the folded conformation that could penetrate the parasite membranes more efficiently and reach the target …”

“…However, the introduction of 2-ferrocenyl-substituted azathia heterocycles caused a notable alteration in the chemical shift of Ar-NH in comparison to the corresponding diamine precursors 2a–d . A remarkable variation of the Ar-NH signal shift in CDCl 3 could be noted for diamines 2a–d that could be most probably attributed to the formation of an intramolecular H-bond in analogue 2b (stable six-membered ring) . A significant shift to higher frequencies (Δδ = 0.61–0.91 ppm) was noted in the case of 4a , 5a , and 6a with the shortest two C-atom linker (Supporting Information Table S2), while an opposite trend was observed for the hybrids with longer linkers.…”

“…falciparum strains at 1 μM. This is an important feature for the development of new antimalarials as it is considered an indicator of susceptibility for cross-resistance development …”

“…This is an important feature for the development of new antimalarials as it is considered an indicator of susceptibility for cross-resistance development. 34 50% inhibitory concentration (in μM) of hybrids vs CQR Dd2 P. falciparum strain determined by LDH assay. Mean ± SD of three independent determinations.…”

Toward Selective Anticancer Agents: Ferrocene‐Steroid Conjugates

“…[9,10] The outcome of substituting a phenyl with a ferrocenyl group might vary in terms of biological response, but some of the key physicochemical properties for pharmacological effectiveness could be expected not to be drastically altered, wherefore the ferrocenyl group is sometimes considered a phenyl bioisostere. [8] Many ferrocene derivatives, some of which reported by us, were found to exhibit antimicrobial, [11][12][13][14][15][16][17][18][19][20]21] antimalarial, [22] anxiolytic, [23] and central nervous system-stimulating activities. [24] Ferrocifens, a group of organometallic analogs of the anticancer drug tamoxifen which are still under formulation studies, [25] and ferroquine, a promising ferrocene-based antimalarial currently in phase II clinical trials, [26,27] represent two major milestones in developing metallocene-containing drugs.…”