Search Results (57)

The purpose of the present study was to evaluate the synergistic effect of two important pharmacophores, 3,4-dihydroxyphenyl and peptidomimetic moieties, as mushroom tyrosinase inhibitors and antimicrobial agents targeting specific strains of pathogenic bacteria. The 3,4-dihydroxybenzaldehyde (protocatechuic aldehyde) was found to be an effective inhibitor of tyrosinase activity, and due to the fact that it is a safe natural substance with such a scaffolded structure, it is likely that dihydroxyl-substituted phenolic derivatives can exhibit potent tyrosinase inhibitory activity. Series of peptidomimetics with an incorporated 3,4-dihydroxyphenyl scaffold was synthesized and characterized. The inhibitory effects of peptidomimetics on a mushroom tyrosinase were studied. The results showed that among the compounds, five of them showed higher inhibitory activity than the parent 3,4-dihydroxybenzyl aldehyde. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the enzymatic pocket for these compounds. Furthermore, the antimicrobial activities of peptidomimetics against selected Gram-positive and Gram-negative bacterial strains (E. coli, A. baumannii, P. aeruginosa, E. cloacae, and S. aureus) were investigated. The results showed that all tested peptidomimetics have antimicrobial activities (MIC values from 0.25 to 4.0 μM) comparable with those observed for the commonly used antibiotics (ciprofloxacin, bleomycin, and cloxacillin). Notably, all evaluated compounds demonstrated significant activity against E. coli and S. aureus strains, which are primary sources of infections resulting in numerous fatalities. Additionally, the cytotoxicity of sixteen derivatives was assessed using the MTT assay on BALB/c3T3 mouse fibroblast cell lines. Cytotoxicity analyses indicated that the tested substances have a similar or reduced impact on cell proliferation compared to commonly utilized antibiotics within the range of therapeutic doses. This study presents the potential of peptidomimetics with 3,4-dihydroxyphenyl scaffolds could be beneficial for developing novel tyrosinase inhibitors and new potent food preservatives or cosmetic additives. Full article

Here, we describe some well-known multicomponent reactions and the progress made over the past decade to make these processes even more environmentally friendly. We focus on the Mannich, Hantzsch, Biginelli, Ugi, Passerini, Petasis, and Groebke–Blackburn–Bienaymé reactions. After describing the origin of the reactions and their mechanisms, we summarize some advances in terms of the eco-compatibility of these different MCRs. These are followed by examples of some reactions, considered as variants, which are less well documented but which are promising in terms of structures generated or synthetic routes. Full article

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure–activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI₅₀ = 0.42–3 μM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI₅₀ in the range of 1–17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI₅₀ vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis. Full article

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC₅₀) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC₅₀), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates. Full article

The Ugi-azide MCR (UA) is one of the most efficient methods for the synthesis of 1,5-disubstituted-1H-tetrazoles (1,5-DS-T). Complex drug-like scaffolds incorporating tetrazoles have demonstrated a wide range of therapeutic benefits such as anti-inflammatory, antiviral, antibiotic, anti-ulcer, anti-anxiety and anti-hypertensive agents, attributable to their mimetic cis amide of peptide bonds that enhance metabolic stability, selectivity and other beneficial physicochemical properties, in addition to their applications in bioimaging, photoimaging and coordination chemistry. Herein, we present the ultrasound-assisted sustainable synthesis of six novel 1,5 DS-T under solvent-free conditions. Full article

The new polyheterocyclic compound, 2-benzyl-7-(4-chlorophenyl)-3-morpholino-6-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, was synthesized by a sequential combination of 4-chlorobenzaldehyde, (1-phenyl-1H-1,2,3-triazol-4-yl)methanamine, 2-isocyano-1-morpholino-3-phenylpropan-1-one, and maleic anhydride under a microwave-assisted one-pot process [Ugi-Zhu/aza Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration] with a 28% overall yield. The synthesized compound was fully characterized by 1D (¹H, ¹³C) and 2D (COSY, HSQC, and HMBC) NMR, FT-IR, and HRMS. Full article

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused synthetic strategy. In both ways, the yields were excellent, considering the high number of bonds formed with release of only one carbon dioxide and two molecules of water. The Ugi-Zhu reaction was carried out using the 4-formylbenzonitrile as orthogonal reagent, where the formyl group was first transformed into the pyrrolo[3,4-b]pyridin-5-one core, and then the remaining nitrile group was further converted into two different nitrogen-containing polyheterocycles, both via click-type cycloadditions. The first one used sodium azide to obtain the corresponding 5-substituted-1H-tetrazolyl-pyrrolo[3,4-b]pyridin-5-one, and the second one with dicyandiamide to synthesize the 2,4-diamino-1,3,5-triazine-pyrrolo[3,4-b]pyridin-5-one. Both synthesized compounds may be used for further in vitro and in silico studies because they contain more than two heterocyclic moieties of high interest in medicinal chemistry, as well as in optics due to their high π-conjugation. Full article

The application of high throughput synthesis methodologies in the generation of active pharmaceutical ingredients (APIs) currently requires the use of automated and easily scalable systems, easy dispensing of supported reagents in solution phase organic synthesis (SPOS), and elimination of purification and extraction steps. The recyclability and recoverability of supported reagents and/or catalysts in a rapid and individualized manner is a challenge in the pharmaceutical industry. This objective can be achieved through a suitable compartmentalization of these pulverulent reagents in suitable devices for it. This work deals with the use of customized polypropylene permeable-capsule devices manufactured by 3D printing, using the fused deposition modeling (FDM) technique, adaptable to any type of flask or reactor. The capsules fabricated in this work were easily loaded “in one step” with polymeric reagents for use as scavengers of isocyanides in the work-up process of Ugi multicomponent reactions or as compartmentalized and reusable catalysts in copper-catalyzed cycloadditions (CuAAC) or Heck palladium catalyzed cross-coupling reactions (PCCCRs). The reaction products are different series of diversely substituted isatins, which were tested in cancerous cervical HeLa and murine 3T3 Balb fibroblast cells, obtaining potent antiproliferative activity. This work demonstrates the applicability of 3D printing in chemical processes to obtain anticancer APIs. Full article

The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists’ interest in the field. It has been widely used in the synthesis of diverse heterocycle molecules such as potential drugs, natural product analogs, pseudo peptides, macrocycles, and functional materials. The Ugi-4CRs involve the use of an amine, an aldehyde or ketone, an isocyanide, and a carboxylic acid to produce an α-acetamido carboxamide derivative, which has significantly advanced the field of isocyanide-based MCRs. The so-called intermediate nitrilium ion could be trapped by a nucleophile such as azide, N-hydroxyphthalimide, thiol, saccharin, phenol, water, and hydrogen sulfide instead of the original carboxylic acid to allow for a wide variety of Ugi-type reactions to occur.β In addition to isocyanide, there are alternative reagents for the other three components: amine, isocyanide, and aldehyde or ketone. All these alternative components render the Ugi reaction an aptly diversity-oriented synthesis of a myriad of biologically active molecules and complex scaffolds. Consequently, this review will delve deeper into alternative components used in the Ugi MCRs, particularly over the past ten years. Full article

New antibiotic agents were prepared using Povarov and Ugi multicomponent reactions upon the known drugs sulfadoxine and dapsone. The prepared derivatives, with increased lipophilicity, showed improved efficiency against Mycolata bacteria. Microbiological guidance for medicinal chemistry is a powerful tool to design new and effective antimicrobials. In this case, the readily synthesized compounds open new possibilities in the search for antimicrobials active on mycolic acid-containing bacteria. Full article

The new polyheterocyclic compound 2-benzyl-3-morpholino-7-(thiophen-2-yl)-6-(thiophen-2-ylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (1) was synthesized via a one-pot process involving an Ugi-Zhu three-component reaction coupled to a cascade aza-Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration process, using toluene as the solvent, ytterbium (III) triflate as the Lewis acid catalyst, and microwave-dielectric heating to increase the overall yield by up to 73%, while decreasing the reaction time to less than one hour. Product 1 was fully characterized by its physicochemical properties and using spectroscopic techniques (IR, HRMS and NMR). Full article

Herein we describe the synthesis of a series of four novel triterpenoid-derived bis-amides, employing masticadienonic acid from Pistacia mexicana as a carboxylic acid component in the Ugi reaction. Products were obtained via a facile and efficient one-pot procedure under mild green conditions, with moderate yields (29–58%). The stereo-electronic nature of the aldehyde component influenced the reaction yields. Full article

A semisynthesis of 6β-acetoxyvouacapane-1,5-disusbtituted tetrazoles derivatives from the leaves of Caesalpinia platyloba by using the Ugi-azide multicomponent reaction as a key step reaction is described. To our knowledge, this is the first report where a non-natural product such as 1,5-disusbtituted tetrazole has been linked to a natural product or derivate of a natural product, and beyond the biological relevance that the target molecules present, this work contributes to the area of natural products as well as multicomponent reactions. Full article

Natural polyamines (PAs) are involved in the processes of proliferation and differentiation of cancer cells. Lipophilic synthetic polyamines (LPAs) induce the cell death of various cancer cell lines. In the current paper, we have demonstrated a new method for synthesis of LPAs via the multicomponent Ugi reaction and subsequent reduction of amide groups by PhSiH₃. The anticancer activity of the obtained compounds was evaluated in the A-549, MCF7, and HCT116 cancer cell lines. For the first time, it was shown that the anticancer activity of LPAs with piperazine fragments is comparable with that of aliphatic LPAs. The presence of a diglyceride fragment in the structure of LPAs appears to be a key factor for the manifestation of high anticancer activity. The findings of the study strongly support further research in the field of LPAs and their derivatives. Full article

The new bis-heterocyclic compound ferrocenyl-bis-(1-(4-benzyl-5-morpholinooxazol-2-yl)-N-(4-(trifluoromethyl)benzyl)methanamine) (1) was synthesized in 73% overall yield in 1.5 hours via a pseudo-repetitive Ugi-Zhu five-component reaction, starting from 1,1′-ferrocenedicarboxaldehyde, 4-(trifluoromethyl)benzylamine, and 2-isocyano-1-morpholino-3-phenylpropan-1-one, in 1:2.1:2.2 proportions, respectively, using scandium(III) triflate as a Lewis-acid catalyst, microwaves as a heat source, and toluene as a solvent. The synthesized compound was characterized by 1D (¹H, ¹³C, and ¹⁹F) and 2D (COSY, HSQC, and HMBC) NMR, HRMS, and FT-IR. Full article