Multicomponent reactions (MCRs) are composed of three or more reagents in which the final product has all or most of the carbon atoms from its starting materials. These reactions represent, in the medicinal chemistry context, great potential in the research for new bioactive compounds, since their products can present great structural complexity. The aim of this review is to present the main multicomponent reactions since the original report by Strecker in 1850 from nowadays, covering their evolution, highlighting their significance in the discovery of new bioactive compounds. The use of MCRs is, indeed, a growing field of interest in the synthesis of bioactive compounds and approved drugs, with several examples of commerciallyavailable drugs that are (or can be) obtained through these protocols.

Multicomponent Reactions for the Synthesis of Bioactive Compounds: A Review

PEG-SO(3)H catalyzed synthesis and cytotoxicity of α-aminophosphonates.

In the present study, for the first time the synthesis of organic–inorganic MCM-41 mesoporous magnetite nanoparticles (MNPs@MCM-41) as a new class of solid acid catalyst with large density of sulfonic acid groups was suggested. The specific surface area and textural property of synthesized nanoparticles were improved through the coupling of inorganic and organic components by template synthesis on the magnetite nanoparticle surface. The new solid acid catalyst was prepared in three steps: (i) preparation of colloidal iron oxide magnetite nanoparticles (Fe3O4 MNPs) with particle size lower than 8.0 nm, (ii) development of an organic–inorganic MCM-41 mesoporous structure with thiol groups on the surface of MNPs (Fe3O4@MCM-41 SH) and (iii) oxidation of thiol groups to sulfonic acid (Fe3O4@MCM-41 SO3H). The incorporation of sulfonic acid as a functional group on the surface of MNPs@MCM-41 was achieved by simultaneous reaction of condensable inorganic silica species and thionilayted organic compounds (co-condensation, one-pot synthesis) that lead to magnetite mesoporous solid acid catalyst. The properties of prepared magnetite nanocomposite were characterized by FT-IR, XRD, UV-DRS, TEM, VSM and titration. Finally, the applicability of the synthesized nanocomposites was tested as heterogeneous solid acid catalyst for one-pot three component synthesis of aryl benzo[α]xanthenone derivatives in room temperature and solvent free conditions.

Organic/inorganic MCM-41 magnetite nanocomposite as a solid acid catalyst for synthesis of benzo[α]xanthenone derivatives

Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediatedmitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models.Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activityof small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compoundswith strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABADenzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediatedmitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown byincreased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial functioneffects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologicdevelopment to target ABAD to improve mitochondrial function.

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Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction

Typical highly porous metal–organic framework (MOFs) materials based on chromium benzenedicarboxylates (Cr-BDC) were prepared through a one-pot hydrothermal synthesis, and were then modified by loading the appropriate ratio of sulfamic acid (SA) using a simple impregnation technique. Pure and modified MIL-101 was characterized by XRD, TEM, SEM and FT-IR measurements. TEM and SEM measurements confirmed that the MIL-101 particles preserved their regular octahedral structure after loading with different weight contents of sulfamic acid. The total number of acid sites and Bronsted to Lewis acid sites ratio (B/L) were examined using potentiometric titration and pyridine adsorption. The acid strength and surface acidity of SA/MIL-101 gradually increased after the modification of Cr-MIL-101 by sulfamic acid crystals up to 55 wt%, then decreased again. The catalytic performance of the solid catalysts was confirmed in the synthesis of 14-phenyl-14H-dibenzo [a,j] xanthene and 7-hydroxy-4-methyl coumarin. In the two reactions, the sample with 55% sulfamic acid loaded on MIL-101 displayed the highest catalytic activity and acidity. The adsorption behaviors of sulfamic acid loaded on MIL-101 materials for methyl orange (MO) as an anionic dye were studied, and were exceptionally suitable for the Langmuir adsorption isotherm. All loaded adsorbents showed high adsorption capacity for methyl orange at 25 °C. The results indicate that the adsorption capacity was modified by changing the amount of sulfamic acid loaded on MIL-101.

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Synthesis of sulfamic acid supported on Cr-MIL-101 as a heterogeneous acid catalyst and efficient adsorbent for methyl orange dye

Polyethyleneglycol bound sulfonic acid (PEG-OSO₃H), a chlorosulphonic acid-modified polyethylene glycol was successfully used as an efficient and eco-friendly polymeric catalyst in the synthesis of 14-aryl/heteroaryl-14H-dibenzo[a,j]xanthenes obtained from the reaction of 2-naphthol and carbonyl compounds under solvent-free conditions with short reaction times and excellent yields. The biological properties of these synthesized title compounds revealed that compounds 3b, 3c, 3f and 3i showed highly significant anti-viral activity against tobacco mosaic virus.

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Design, synthesis and antiviral potential of 14-aryl/heteroaryl-14H-dibenzo[a,j]xanthenes using an efficient polymer-supported catalyst.

The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1 H, 13 C, 31 P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.

Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)

A series of new diethyl(alkyl/aryl/heteroarylamino)(4-(pyridine-2-yl)phenyl)methylphosphonates (4a-t) were synthesized via three-component Kabachnik-Field's reaction of 4-(pyridin-2-yl)benzaldehyde, diethylphosphite and various primary amines, catalyzed by cupric acetate monohydrate [Cu(OAc)(2) ∙ H(2)O] under solvent-free and microwave irradiation conditions. Their computational docking analysis supported them as good therapeutic agents to the breast cancer aromatase enzyme and ascertained 4a, 4h, 4m, 4n, and 4t as potential molecules with good binding affinities varying from -9.0 to -9.6 kcal/mol and containing the 4-(pyridine-2-yl)phenyl moiety as a pharmacophore. Their in vitro screening performed for the anti-cell proliferation activity against MBC-MCF7 cells by MTT and Trypan blue assays confirmed 4m, 4n, and 4q as promising compounds to sustain a low percentage of cell viability at 20 µg/mL concentration. These compounds were also evaluated for their antioxidant activity by the DPPH method and the results established that compounds 4m, 4n, and 4q show around 10% higher activity than the standard antioxidant ascorbic acid.

Design, synthesis, antioxidant, and anti-breast cancer activities of novel diethyl(alkyl/aryl/heteroarylamino)(4-(pyridin-2-yl)phenyl)methylphosphonates.

Solvent-free synthesis of α-aminophosphonates: Cellulose-SO3H as an efficient catalyst

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Balam Satheesh Krishna

Papers

Design, synthesis and antiviral potential of 14-aryl/heteroaryl-14H-dibenzo[a,j]xanthenes using an efficient polymer-supported catalyst.

Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)

Design, synthesis, antioxidant, and anti-breast cancer activities of novel diethyl(alkyl/aryl/heteroarylamino)(4-(pyridin-2-yl)phenyl)methylphosphonates.

Solvent-free synthesis of α-aminophosphonates: Cellulose-SO3H as an efficient catalyst

Cellulose-SO3H catalyzed synthesis of bis(α-aminophosphonates) and their antioxidant activity