As a member of the class I PI3K family, phosphoinositide 3-kinase (PI3K) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity.
View Article and Find Full Text PDFRSC Adv
November 2022
Herein, we describe the development of a green, scalable flow Pd-catalyzed aerobic oxidation for the key step in the synthesis of CPL302415, which is a new PI3K inhibitor. Applying this environmental-friendly, sustainable catalytic oxidation we significantly increased product yield (up to 84%) and by eliminating of workup step, we improved the waste index and E factor (up to 0.13) in comparison with the stoichiometric synthesis.
View Article and Find Full Text PDFPhosphoinositide 3-kinase (PI3K), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-]pyrimidine with IC values in the low nanomolar range and high selectivity against the PI3K isoform.
View Article and Find Full Text PDFPhosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: , , , ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K, displaying IC values ranging from 1.
View Article and Find Full Text PDFβ-Hydroxy sulfones are important in organic synthesis. The simplest method of β-hydroxy sulfones synthesis is the hydrogenation of β-keto sulfones. Herein, we report the reducing properties of alkyl aluminum compounds RAl (R = Et, -Bu, -Bu, -Bu and -Hex); -BuAlH; EtAlCl and EtAlCl in the hydrogenation of β-keto sulfones.
View Article and Find Full Text PDFDespite considerable progress in the multifaceted chemistry of non-redox-metal alkylperoxides, the knowledge about magnesium alkylperoxides is in its infancy and only started to gain momentum. Harnessing the well-defined dimeric magnesium tert-butylperoxide [(BDI)Mg(μ-η:η-OOtBu)] incorporating a fluorinated β-diketiminate ligand, herein, we demonstrate its transformation at ambient temperature to a spiro-type, tetranuclear magnesium alkylperoxide [(BDI)Mg(μ-OOtBu)]. The latter compound was characterized by single-crystal X-ray diffraction and its molecular structure can formally be considered as a homoleptic magnesium tert-butylperoxide [Mg(µ-OOtBu)] terminated by two monomeric magnesium tert-butylperoxides.
View Article and Find Full Text PDFFormylation of ansa[4]-ferrocene, obtained through the ruthenium-catalysed olefin metathesis, yields two separable, planar chiral 1,3- and 1,2-ansa-ferrocene aldehydes. Single-crystal X-ray structure analysis reveals that both regioisomers crystallize with spontaneous resolution of the racemate in the chiral P212121 space group with one molecule in the asymmetric unit. The major 1,3-isomer was further transformed into a conjugate with 1,2,3-triazole and uracil using "click" chemistry as the key synthetic step.
View Article and Find Full Text PDFSince our study showed that sulfone derivatives' action mode creates a lesser risk of inducing widespread resistance among Candida spp., we continued verifying sulfones' antifungal activity using the following newly synthesized derivatives: bromodichloromethy-4-hydrazinyl-3-nitrophenyl sulfone (S1), difluoroiodomethyl-4-hydrazinyl-3-nitrophenyl sulfone (S2), and chlorodifluoromethyl-4-hydrazinyl-3-nitrophenyl sulfone (S3). As the mechanism by which sulfones gain access to the cytoplasm has not been elucidated yet, in order to track S1-3, we coupled their hydrazine group with BODIPY (final S1-3 BODIPY-labelled were named SB1-3).
View Article and Find Full Text PDFCandida albicans represents an interesting microorganism to study complex host-pathogen interactions and for the development of effective antifungals. Our goal was to assess the efficacy of 4-chloro-3-nitrophenyldifluoroiodomethyl sulfone (named Sulfone) against the C. albicans infections in the Galleria mellonella host model.
View Article and Find Full Text PDFSince candidiasis is so difficult to eradicate with an antifungal treatment and the existing antimycotics display many limitations, hopefully new sulfone derivatives may overcome these deficiencies. It is pertinent to study new strategies such as sulfone derivatives targeting the virulence attributes of C. albicans that differentiate them from the host.
View Article and Find Full Text PDFWe investigated the role of , , , and in the virulence of under a novel compound 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone (Compound ). We examined whether the exposure of cells to Compound , non-cytotoxic to mammalian cells, reduces their adhesion to the human epithelium. We next assessed whether the exposure of cells to Compound modulates the anti-inflammatory response (IL-10) and induces human macrophages to respond to the cells.
View Article and Find Full Text PDFReactions between O and organometallics with non-redox-active metal centers have received continuous interest for over 150 years, although significant uncertainties concerning the character and details of the actual mechanism of these reactions persist. Harnessing dinuclear three-coordinate alkylzinc derivatives of an N,N-coupled bis(β-diketimine) proligand (LH ) as a model system, we demonstrate for the first time that a slight modification of the reaction conditions might have a dramatic influence on the oxygenation reaction outcomes, leading to an unprecedented variety of products originating from a single reaction system, that is, partially and fully oxygenated zinc alkoxides, zinc alkylperoxides, and zinc hydroxide compounds. Our studies indicate that accessibility of the three-coordinate zinc center by the O molecule, coupled with the lower reactivity of Zn-Me vs.
View Article and Find Full Text PDFAim: The effect of KEX2 mutations on C. albicans virulence and resistance to halogenated methyl sulfones was assessed.
Materials & Methods: The mechanism of action of sulfones was studied using flow cytometry and microscopy.
Despite the fact that extensive research has been carried out, the oxygenation of alkyl magnesium species still remains a highly unexplored research area and significant uncertainties concerning the mechanism of these reactions and the composition of the resulting products persist. This case study compares the viability of the controlled oxygenation of alkylmagnesium complexes supported by β-diketiminates. The structural tracking of the reactivity of (N,N)MgR-type complexes towards O at low temperature showed that their oxygenation led exclusively to the formation of magnesium alkylperoxides (N,N)MgOOR.
View Article and Find Full Text PDFWe investigated the antifungal activity of novel a 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone (compound 4). The synthesis of compound 4 was commenced from sodium 4-chlorobenzene sulfinate and the final product was obtained by treatment of α-chloro-β-keto-sulfone with sodium hypobromite. The sensitivity of 63 clinical isolates belonging to the most relevant Candida species toward compound 4 using the method M27-A3 was evaluated.
View Article and Find Full Text PDFCandida species are the major opportunistic human pathogens accounting for 70-90% of all invasive fungal infections. Candida spp, especially C. albicans, are able to produce and secrete hydrolytic enzymes, particularly aspartic proteases (Saps).
View Article and Find Full Text PDFThis paper reports a series of comparative experiments on the activity of carbon- and oxygen-centred radical species in a model reaction of the radical addition of THF to imines mediated by a series of zinc alkyl/air reaction systems. The study strongly contradicts the notion that generally R˙ radicals are the initiating species in organic reactions mediated by R M/air systems, and simultaneously demonstrates that oxygen-centred radical species are the key intermediates responsible for the initiation process. In addition, a new efficient RZn(L)/air initiating system for radical organic reactions exampled by a model reaction of radical addition of THF to imines is developed.
View Article and Find Full Text PDFArch Pharm (Weinheim)
February 2015
The influence of halogenated methyl sulfones, i.e. bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named halogenated methyl sulfone 1), dichloromethyl-4-chloro-3-nitrophenyl sulfone (halogenated methyl sulfone 2), and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (halogenated methyl sulfone 3), on cell growth inhibition, aspartic protease gene (SAP4-6) expression, adhesion to epithelium, and filamentation was investigated.
View Article and Find Full Text PDFThe successful preventing and effective treatment of invasive Candida albicans infections required research focused on synthesis of new classes of agents and antifungal activity studies. Bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named compound 6); dichloromethyl-4-chloro-3-nitrophenyl sulfone (named 7); and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (named 11) on inhibition of planktonic cells' growth, leucine arylamidase APE2 gene expression, and adhesion to epithelial cells were investigated. In vitro anti-Candida activities were determined against wild-types, and the morphogenesis mutants: Δefg1 and Δcph1.
View Article and Find Full Text PDFWorld J Microbiol Biotechnol
September 2014
Fungal virulence factors represent a strategy for the design of new compounds with effective activities against Candida spp. Dichloromethyl-4-chloro-3-nitrophenylsulfone (named Compound 1) and chlorodibromomethyl-4-hydrazino-3-nitrophenylsulfone (Compound 2) versus Candida albicans virulence factors (SAP2 expression and adhesion to Caco-2 cell line) were investigated. Candida albicans SC5314 and its mutants: Δsap9, Δsap10, Δsap9/10 were used.
View Article and Find Full Text PDFA series of 5-halogenomethylsulfonylbenzimidazole and benzotriazole derivatives was synthesized as potential antibacterial agents. A new method of synthesis of benzimidazoles was developed. The antimicrobial activities of these compounds were tested against a series of reference and clinical strains.
View Article and Find Full Text PDFA halogenmethylsulfonyl moiety is incorporated in numerous active herbicides and fungicides. The synthesis of tribromomethyl phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different synthetic routes, starting from 4-chlorothiophenol or 4-halogenphenyl methyl sulfone.
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