Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gramnegative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.
The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.
The mono-alkylation of 1,3-diketones using alcohols is possible in the presence of catalytic amounts of Ru(CO)(PPh3)3HCl and 10% mol of the Hantzsch ester. The borrowing hydrogen process between the catalyst and the dihydropyridine/pyridine couple prevents the common double alkylation of the Knoevenagel adduct without the need of stoichiometric reducing agents or sacrificial nucleophiles. The reaction was applied to the synthesis of a lactone intermediate for the preparation of the anti-obesity drug orlistat. Moreover, under the same Ru catalysis, a Friedländer reaction occurred with o-amino benzyl alcohols giving access to different 3-keto-substituted quinolines
Systemic fungal infections are, nowadays, of crucial importance and, thus, in the last decade, we explored the great potential of natural and synthetic guanylated compounds, a great amount of work that led to the development of new non-azole antifungal compounds bearing a macrocycle, endowed with potent antifungal activity. We planned many biological assays to evaluate this class, implying always greater amount of compounds needed. This triggered us to setup a convenient strategy to prepare, in an easy and affordable way, grams of compound to be tested in excellent overall yield.
Our research group has been involved for a long time
in the development
of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic
investigation drove us to perform an in silico target
fishing study, which allowed the identification of chitinases as one
of their putative targets, with 1a showing a submicromolar
inhibition of Trichoderma viride chitinase. In this
work, we investigated the possibility to further inhibit the corresponding
human enzymes, acidic mammalian chitinase (AMCase) and chitotriosidase
(CHIT1), involved in several chronic inflammatory lung diseases. Thus,
we first validated the inhibitory activity of 1a against
AMCase and CHIT1 and then designed and synthesized new derivatives
aimed at improving the potency and selectivity against AMCase. Among
them, compound 3f emerged for its activity profile along
with its promising in vitro ADME properties. We also
gained a good understanding of the key interactions with the target
enzyme through in silico studies.
Treatment against tuberculosis can lead to the selection
of drug-resistant Mycobacterium tuberculosis strains. To tackle this
serious threat, new targets from M. tuberculosis are needed to develop novel effective drugs. In this work, we aimed
to provide a possible workflow to validate new targets and inhibitors
by combining genetic, in silico, and enzymological
approaches. CanB is one of the three M. tuberculosis β-carbonic anhydrases that catalyze the reversible reaction
of CO2 hydration to form HCO3
– and H+. To this end, we precisely demonstrated that CanB
is essential for the survival of the pathogen in vitro by constructing conditional mutants. In addition, to search for
CanB inhibitors, conditional canB mutants were also
constructed using the Pip-ON system. By molecular docking and minimum
inhibitory concentration assays, we selected three molecules that
inhibit the growth in vitro of M.
tuberculosis wild-type strain and canB conditional mutants, thus implementing a target-to-drug approach.
The lead compound also showed a bactericidal activity by the time-killing
assay. We further studied the interactions of these molecules with
CanB using enzymatic assays and differential scanning fluorimetry
thermal shift analysis. In conclusion, the compounds identified by
the in silico screening proved to have a high affinity
as CanB ligands endowed with antitubercular activity.
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