Multicomponent and Domino Reactions in Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (22 February 2024) | Viewed by 10765

Special Issue Editors

Departamento de Química Orgánica I, Centro de Investigación y Estudios Avanzados “Lucio Lascaray”- Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
Interests: organic synthesis; organophosphorus chemistry; fluorine chemistry; heterocyclic chemistry; cycloaddition reactions; solid-phase synthesis; design and development of enzyme inhibitors; drug discovery (cancer and neglected tropical diseases)
Campus Álava, Universidad del Pais Vasco - Euskal Herriko Unibertsitatea, San Sebastián, Spain
Interests: development of new synthetic methodologies, which includes the chemistry of nitrogen- and phosphorus-containing compounds for the preparation of acyclic and cyclic compounds; the discovery of new organocatalytic processes for the synthesis of small chiral organic molecules
Universidad del Pais Vasco - Euskal Herriko Unibertsitatea, Campus Álava, Vitoria-Gasteiz, Spain
Interests: design, synthesis and development of new methodologies in organic synthesis of heterocyclic compounds; the medicinal chemistry of anticancer, antileishmanial drugs
Campus Álava, Universidad del Pais Vasco - Euskal Herriko Unibertsitatea, Vitoria-Gasteiz, Spain
Interests: preparation of new enantiopure amino acid and aminophosphonic acid derivatives using organocatalytic processes; the development of new multicomponent reactions

Special Issue Information

Dear Colleagues,

The generation of new chemical entities that can serve as potential drug candidates is a key step in the drug discovery process. Successful drug development requires efficient, short and low-cost synthetic methodologies for lead discovery. In this regard, multicomponent reactions (MCRs) and domino reactions have emerged as a powerful new strategy in synthetic organic chemistry and drug discovery, providing a more efficient (fewer steps) and quicker way (less time) to prepare molecular diversity and complexity than methods used in traditional chemistry.

MCRs are defined as one-pot processes in which three or more components react in one synthetic operation to form a single product in a selective way. According to Tietze's definition, a domino reaction is understood as “a process involving two or more consecutive reactions in which subsequent reactions result as a consequence of the functionality formed by bond formation or fragmentation in the previous step”. These reactions are atom-economic, step-efficient, convergent, and they have high exploratory power with regard to chemical space. They are therefore useful alternatives to sequential multistep synthesis, and ideally suited for the generation of compound libraries.

Due to their versatility, MCRs and domino reactions have found applications in many fields of organic chemistry and in medicinal chemistry in particular. The synthetic community in industry and academia has recognized the easy and quick access to biologically relevant compounds by MCRs and domino reactions as preferred methods in the drug discovery process.

The Special Issue “Multicomponent and Domino Reactions in Drug Discovery” will acknowledge research papers with topics including, but not limited to, recent applications in the design, synthesis and in vitro evaluation of new complex molecules with often biologically relevant scaffold structures developed by multicomponent (MCRs) and domino reactions. Review articles and future perspectives shedding light on developments in the field are also welcome.

Prof. Dr. Francisco Palacios
Dr. Jesús Manuel de Los Santos
Dr. Concepción Alonso
Dr. Javier Vicario
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • medicinal chemistry
  • drug synthesis
  • multicomponent reactions
  • domino reactions, bioactivity
  • SAR studies
  • hybrid drugs

Published Papers (3 papers)

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Research

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19 pages, 13808 KiB  
Article
Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group
by Xabier del Corte, Adrián López-Francés, Ilia Villate-Beitia, Myriam Sainz-Ramos, Edorta Martínez de Marigorta, Francisco Palacios, Concepción Alonso, Jesús M. de los Santos, José Luis Pedraz and Javier Vicario
Pharmaceuticals 2022, 15(5), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050511 - 22 Apr 2022
Cited by 7 | Viewed by 2095
Abstract
We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human [...] Read more.
We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism. Full article
(This article belongs to the Special Issue Multicomponent and Domino Reactions in Drug Discovery)
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Review

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42 pages, 13456 KiB  
Review
Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients
by Ángel Cores, José Clerigué, Emmanuel Orocio-Rodríguez and J. Carlos Menéndez
Pharmaceuticals 2022, 15(8), 1009; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15081009 - 17 Aug 2022
Cited by 17 | Viewed by 3681
Abstract
Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less [...] Read more.
Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthesis offers significant advantages in terms of synthetic efficiency. This review provides a critical summary of the use of multicomponent reactions for the preparation of active pharmaceutical principles. Full article
(This article belongs to the Special Issue Multicomponent and Domino Reactions in Drug Discovery)
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63 pages, 22384 KiB  
Review
Synthesis of 3,4-Dihydropyrimidin(thio)one Containing Scaffold: Biginelli-like Reactions
by Francisco Sánchez-Sancho, Marcos Escolano, Daniel Gaviña, Aurelio G. Csáky, María Sánchez-Roselló, Santiago Díaz-Oltra and Carlos del Pozo
Pharmaceuticals 2022, 15(8), 948; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080948 - 30 Jul 2022
Cited by 10 | Viewed by 3937
Abstract
The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two [...] Read more.
The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two main approaches have been devised. The first one involves the modification of the conventional components of the Biginelli reaction and the second one refers to the postmodification of the Biginelli products. Both strategies have been extensively revised in this manuscript. Regarding the first one, initially, the modification of one of the components was covered. Although examples of modifications of the three of them were described, by far the modification of the keto ester counterpart was the most popular approach, and a wide variety of different enolizable carbonylic compounds were used; moreover, changes in two or the three components were also described, broadening the substitution of the final dihydropyrimidines. Together with these modifications, the use of Biginelli adducts as a starting point for further modification was also a very useful strategy to decorate the final heterocyclic structure. Full article
(This article belongs to the Special Issue Multicomponent and Domino Reactions in Drug Discovery)
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