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12 pages, 1988 KiB

Open AccessArticle

The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors

by Christina A. Gates, Donald S. Backos, Philip Reigan and Nicholas R. Natale

Molecules 2023, 28(19), 6800; https://doi.org/10.3390/molecules28196800 - 25 Sep 2023

Viewed by 1076

Abstract

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR_1a, mGluR₅, or mGluR₈. Additional analogs were [...] Read more.

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR_1a, mGluR₅, or mGluR₈. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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16 pages, 4171 KiB

Open AccessArticle

Structural Optimization of BIPPO Analogs as Potent Antimalarials

by Yang Zheng, An Matheeussen, Louis Maes, Guy Caljon, Geert Jan Sterk and Rob Leurs

Molecules 2023, 28(13), 4939; https://doi.org/10.3390/molecules28134939 - 23 Jun 2023

Cited by 1 | Viewed by 1294

Abstract

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the [...] Read more.

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC₅₀ 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC₅₀ 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC₅₀ > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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34 pages, 9727 KiB

Open AccessArticle

Schiff Bases and Stereocontrolled Formation of Fused 1,3-Oxazolidines from 1-Amino-2-Indanol: A Systematic Study on Structure and Mechanism

by Esther Matamoros, Mark E. Light, Pedro Cintas and Juan C. Palacios

Molecules 2023, 28(4), 1670; https://doi.org/10.3390/molecules28041670 - 9 Feb 2023

Cited by 1 | Viewed by 2260

Abstract

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses [...] Read more.

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses and DFT-based calculations on imine/enamine tautomerism in the solid state and solution. In the course of imine formation, a pentacyclic oxazolidine–oxazine structure could be isolated with complete stereocontrol, whose configuration has been determined by merging theory and experiment. Mechanistic studies reveal that, although oxazolidines can be obtained under kinetic conditions, the prevalence of imines obeys to thermodynamic control as they are the most stable structures. The stereochemical outcome of imine cyclization under acylating conditions leads to formation of 2,4-trans-oxazolidines. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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12 pages, 3364 KiB

Open AccessArticle

Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design

by Renate Griffith and John B. Bremner

Molecules 2023, 28(4), 1631; https://doi.org/10.3390/molecules28041631 - 8 Feb 2023

Cited by 4 | Viewed by 1416

Abstract

As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range [...] Read more.

As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp² hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the N^…Y interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH₃ (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp³ hybridised carbon (Y = CH₂). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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12 pages, 2188 KiB

Open AccessArticle

Acid-Triggered Switchable Near-Infrared/Shortwave Infrared Absorption and Emission of Indolizine-BODIPY Dyes

by Matthew A. Saucier, Cameron Smith, Nicholas A. Kruse, Nathan I. Hammer and Jared H. Delcamp

Molecules 2023, 28(3), 1287; https://doi.org/10.3390/molecules28031287 - 29 Jan 2023

Cited by 3 | Viewed by 3895

Abstract

Fluorescent organic dyes that absorb and emit in the near-infrared (NIR, 700–1000 nm) and shortwave infrared (SWIR, 1000–1700 nm) regions have the potential to produce noninvasive high-contrast biological images and videos. BODIPY dyes are well known for their high quantum yields in the [...] Read more.

Fluorescent organic dyes that absorb and emit in the near-infrared (NIR, 700–1000 nm) and shortwave infrared (SWIR, 1000–1700 nm) regions have the potential to produce noninvasive high-contrast biological images and videos. BODIPY dyes are well known for their high quantum yields in the visible energy region. To tune these chromophores to the NIR region, fused nitrogen-based heterocyclic indolizine donors were added to a BODIPY scaffold. The indolizine BODIPY dyes were synthesized via microwave-assisted Knoevenagel condensation with indolizine aldehydes. The non-protonated dyes showed NIR absorption and emission at longer wavelengths than an aniline benchmark. Protonation of the dyes produced a dramatic 0.35 eV bathochromic shift (230 nm shift from 797 nm to 1027 nm) to give a SWIR absorption and emission (λ_max^emis = 1061 nm). Deprotonation demonstrates that material emission is reversibly switchable between the NIR and SWIR. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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12 pages, 2044 KiB

Open AccessArticle

A New Tetracyclic Bromopyrrole-Imidazole Derivative through Direct Chemical Diversification of Substances Present in Natural Product Extract from Marine Sponge Petrosia (Strongylophora) sp.

by Natchanun Sirimangkalakitti, Kazuo Harada, Makito Yamada, Masayoshi Arai and Mitsuhiro Arisawa

Molecules 2023, 28(1), 143; https://doi.org/10.3390/molecules28010143 - 24 Dec 2022

Cited by 1 | Viewed by 2123

Abstract

Chemical diversification of substances present in natural product extracts can lead to a number of natural product-like compounds with a better chance of desirable bioactivities. The aim of this work was to discover unprecedented chemical conversion and produce new compounds through a one-step [...] Read more.

Chemical diversification of substances present in natural product extracts can lead to a number of natural product-like compounds with a better chance of desirable bioactivities. The aim of this work was to discover unprecedented chemical conversion and produce new compounds through a one-step reaction of substances present in the extracts of marine sponges. In this report, a new unnatural tetracyclic bromopyrrole-imidazole derivative, rac-6-OEt-cylindradine A (1), was created from a chemically diversified extract of the sponge Petrosia (Strongylophora) sp. We also confirmed that 1 originated from naturally occurring (-)-cylindradine A (2) via a new reaction pattern. Moreover, (-)-dibromophakellin (3) and 4,5-dibromopyrrole-2-carboxylic acid (4), as well as 2, were reported herein for the first time in this genus. Studies on the possible reaction mechanism and bioactivities were also conducted. The results indicate that the direct chemical diversification of substances present in natural product extracts can be a speedy and useful strategy for the discovery of new compounds. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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Review

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15 pages, 1859 KiB

Open AccessReview

Biological Activity of Hexaazaisowurtzitane Derivatives

by Daria A. Kulagina, Sergey V. Sysolyatin, Svetlana G. Krylova, Elena A. Kiseleva, Tatiana N. Povetyeva, Elena P. Zueva, Valeria V. Eremina, Natalia A. Alekseeva, Svetlana V. Strokova, Nikolai I. Suslov and Vadim V. Zhdanov

Molecules 2023, 28(24), 8084; https://doi.org/10.3390/molecules28248084 - 14 Dec 2023

Cited by 1 | Viewed by 1309

Abstract

Biologically active compounds of natural or synthetic origin have a complex structure and generally contain various structural groups among which polycyclic cage amines are found. Hexaazaisowurtzitanes are representatives of these amines and studies on their biological activity began less than two decades ago, [...] Read more.

Biologically active compounds of natural or synthetic origin have a complex structure and generally contain various structural groups among which polycyclic cage amines are found. Hexaazaisowurtzitanes are representatives of these amines and studies on their biological activity began less than two decades ago, starting with research on the environmental impact of CL-20. This research helped to evaluate the risks of potential pollution in the habitat environments of living organisms and determine whether the chemical compounds in question could be utilized in pesticides, herbicides, fungicides, or medicinal drugs. The nomenclature of hexaazaisowurtzitane compounds has recently been expanded significantly, and some of them have demonstrated promise in the design of medicinal drugs. This paper review studies the pharmacological activity of the acyl derivatives of hexaazaisowurtzitane. Most of the compounds have been found to possess a high analgesic activity, providing a solution to the pressing issue of pain management in current pharmacology. Analgesic drugs currently used in the clinical practice do not meet all of the efficacy and safety requirements (gastro-, nephro-, hepato-, haematotoxicity, etc.). The material presented in the seven sections of this paper highlights information about hexaazaisowurtzitane derivatives. Furthermore, they have been observed to exhibit anti-inflammatory, anticonvulsant, antihypoxic, and antimetastatic activities, which render them highly promising for evaluation in various fields of medicinal practice. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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37 pages, 28840 KiB

Open AccessReview

Recent Advances in N-Heterocyclic Small Molecules for Synthesis and Application in Direct Fluorescence Cell Imaging

by Yanan Li, Tao Liu and Jianan Sun

Molecules 2023, 28(2), 733; https://doi.org/10.3390/molecules28020733 - 11 Jan 2023

Cited by 18 | Viewed by 3056

Abstract

Nitrogen-containing heterocycles are ubiquitous in natural products and drugs. Various organic small molecules with nitrogen-containing heterocycles, such as nitrogen-containing boron compounds, cyanine, pyridine derivatives, indole derivatives, quinoline derivatives, maleimide derivatives, etc., have unique biological features, which could be applied in various biological fields, [...] Read more.

Nitrogen-containing heterocycles are ubiquitous in natural products and drugs. Various organic small molecules with nitrogen-containing heterocycles, such as nitrogen-containing boron compounds, cyanine, pyridine derivatives, indole derivatives, quinoline derivatives, maleimide derivatives, etc., have unique biological features, which could be applied in various biological fields, including biological imaging. Fluorescence cell imaging is a significant and effective imaging modality in biological imaging. This review focuses on the synthesis and applications in direct fluorescence cell imaging of N-heterocyclic organic small molecules in the last five years, to provide useful information and enlightenment for researchers in this field. Full article

(This article belongs to the Special Issue Fused-Nitrogen-Containing Heterocycles and Their Biological Properties)

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