Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design

Abstract

In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research.

Keywords: bioprobes; drug discovery; heterocycles; multicomponent reactions; reaction discovery.

Figure 1

Heterocycle-based MCRs for MedChem applications.

Figure 2

AChE inhibitors. (a) Outline of the AChE dual inhibition. (b) The Povarov MCR and subsequent oxidation leading to the new peripheral site inhibitors. (c) Structure and pharmacological data for the dual AChE inhibitor 2a. (d) Docking simulation showing the interactions at the catalytic and peripheral sites. From ref. [28] (P. Camps et al., J. Med. Chem. 2009, 52, 5365), reproduced with permission. Copyright 2009 ACS. (e) Isosteric modification in the peripheral site inhibitor core. (f) Structure and pharmacological data of small molecule peripheral site inhibitor 3a. (g) Structure and pharmacological data for the dual AChE inhibitor 3b.

Figure 3

DHFR inhibitors. (a) Concept of the Drugs form Drugs approach. (b) Structure of trimethoprim and GBBR leading to mono- and bis- adducts 4 and 5, respectively. (c) Structure and activity data of lead compound 4a. (d) Growth curve of E. coli with TMP and 4a in combination with SMX. (e) Docked position of adduct 4a (yellow) in DHFR (homology model from E. coli). The location of TMP (orange) and NADPH (gray) is also shown.

Figure 4

AhR Activators. (a) The extended GBBRs with indole carboxaldehydes. (b) FICZ ligand structure. (c) Novel MCR-based indolocarbazole ligands. (d) The AhR-activating properties of the synthesized compounds in keratinocytes (related to cytochrome P450 activity and expression). * p ≤ 0.05.

Figure 5

MCR-based antiparasitic agents. (a) Imidazolium salt MLB with antiparasitic activity against Chagas disease. (b) MCR pathway to tetrasubstituted imidazolium salts. (c) Biological activities of promising derivatives. (d) Benzimidazolium salt MLJ with mild antiparasitic activity against Chagas disease. (e) TMSCl-promoted MCR synthesis of benzimidazolium salts. (f) Biological activities of selected derivatives.

Figure 6

GBBR approach to antivirals. (a) Selective GBBRs upon diaminoazines. (b) Antiviral activity of the representative GBBR compounds against human Adenovirus.

Figure 7

(a) Structure and photophysical properties of the BODIPY core. (b) Isocyanide derivatized BODIPY scaffold and generation of compounds 15 through various IMCRs. (c) Structure and photophysical properties of selected probe 15a, Phagogreen. (d) Co-incubation of 15a and LysoTracker Red in A549 cells. (e) RAW 264.7 macrophages were treated with 15a. Fluorescence of 15a in (I) non-activated macrophages, (II) zymosan-activated macrophages, and (III) zymosan-activated macrophages treated with bafilomycin A. (f) Still from time-lapse imaging of transgenic zebrafish with m-Cherry-labelled macrophages treated with PhagoGreen. Scale bars: 20 μm. Sections (d–f) from ref. [47] (O. Vázquez-Romero et al, J. Am. Chem. Soc. 2013, 135, 16018) reproduced with permission. Copyright 2013 ACS. (g) GBBR access to BODIPY-adduct 17. (h) Human A549 epithelial cells upon incubation with compound 17 and MitoTracker Red. Scale bar: 10 µm. (i) Fluorescent properties of probe 17 vs. GBBR adduct 16. Sections (h,i) From ref. [32] (O. Ghashghaei et al., Chem. Eur. J. 2018, 24, 14513), reproduced with permission Copyright Wiley-VCH GmbH.

Figure 8

(a) MCR access to probe 18 for imaging of histamine in live cells. (b) Normalized fluorescence of probe 18 (black) and histamine adduct 19 (blue). (c) Microscopy images of: (a) RBL-2H3 basophils upon incubation of probe 18 with DRAQ5 as nuclear counterstaining; (b) RAW 264.7 macrophages after incubation with Histamine blue and upon histamine uptake and (c) after treatment with thapsigargin. Sections (b,c) from ref [48] (N. Kielland et al., Chem. Commun. 2012, 48, 7401) reproduced with permission form the Royal Society of Chemistry. (d) MCR to the BODIPY dipolar acid fluoride 21. (e) Structure of probe 22, from conjugation of 21 with natamycin. (f) Fluorescent properties of probe 22 in 1,4-dioxane and in PBS. (g) Fluorescence images of fungal and bacterial cells upon incubation with 20: (a) F. solani, (b) F. oxysporum, (c) A. flavus and (d) P. Aeruginosa. Scale bar: 20 μm. Sections (f,g) from ref [50] (M. Sintes et al. Bioconjug. Chem. 2016, 27, 1340) reproduced with permission. Copyright 2016 ACS.

Figure 9

I₂ Imidazoline receptors. (a) Structure of known I₂IR ligands. (b) MCR access to substituted 2-imidazolines 23. (c) Structure and binding affinities of the selected compounds. (d) In vivo data of compound 23b. (e) Condensation between maleimides and PhosMIC derivatives leading to new I₂-IR ligands 24. (f) 3D-QSAR series 24. (g) Structure of the selected analogue 24a. Values represented in (d) are mean ± Standard error of the mean (SEM); n = 36 (SR1-Ct n = 11; SP8-Ct n = 11; SP8-23b n = 14). ** p < 0.01; *** p < 0.001.