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Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 21290

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Prof. Dr. Costel Moldoveanu

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Chemistry Department, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania
Interests: diazoles; medicinal chemistry; anticancer; antituberculosis; ultrasounds; microwave; organic synthesis
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Dear Colleagues,

Heterocyclic compounds are such an important class of organic compounds that they have their own nomenclature and numbering system. The importance of these compounds derives from the fact that most heterocyclic compounds have biological activity. In fact, nucleic acids, which are the basis for the transmission of genetic information, are natural macromolecular compounds. The monomers from which these macromolecular compounds are derived have a nitrogenous base in their composition. Five heterocyclic compounds derived from purine (adenine and guanine) and pyrimidine (cytosine, thymine, and uracil) are known as nitrogenous bases.

The pharmaceutical industry and modern medicinal science put a lot of effort into their combat with two aggressive life-threatening diseases: cancer and tuberculosis (TB). Both diseases are leading causes of death worldwide, millions of people dying every year; the incidence of both are continually increasing, and the treatments become more and more complicated and sophisticated. The cancer chemotherapy is complex, expensive, and often rather inefficient, because of the large variety of neoplasm types, high toxicity levels, non-specificity of drugs, and the emergence of drug resistance and multidrug-resistance (MDR). On the other hand, because of the Mycobacterium tuberculosis (Mtb) versatility, the treatment against TB has become a challenging and difficult task, and the situation has become even worse because of the phenomena of drug resistance, MDR, extensively drug-resistant (XDR), association of TB with AIDS, etc. It is well known from the literature that imidazole (and its benzo-derivative benzimidazole) and pyridine (and its benzoderivative quinoline) derivatives are core scaffolds widely present in many classes of drugs (of natural or synthetic origin), displaying a large variety of interesting biological activities (antimicrobials, antifungus, anti-inflammatory, antihypertensive, antineuropathic, antihistaminic, etc.; anticancer and anti-TB are also included).

The aim of this Special Issue is to provide a platform to present the latest developments focused on the synthesis of biological active heterocycle derivatives especially (but not only) with anticancer, anti-tuberculosis, and antimicrobial properties.

Prof. Dr. Costel Moldoveanu
Guest Editor

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Keywords

heterocycles
azines
azoles
anticancer
anti-tuberculosis
antimicrobial
growth factors

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Published Papers (12 papers)

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Research

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18 pages, 2678 KiB

Open AccessArticle

When Chirality Makes the Difference: The Case of Novel Enantiopure N-Heterocyclic Carbene–Gold and –Silver Complexes

by Maria Marra, Annaluisa Mariconda, Domenico Iacopetta, Jessica Ceramella, Assunta D’Amato, Camillo Rosano, Kateryna Tkachenko, Michele Pellegrino, Stefano Aquaro, Maria Stefania Sinicropi and Pasquale Longo

Molecules 2024, 29(22), 5262; https://doi.org/10.3390/molecules29225262 - 7 Nov 2024

Viewed by 474

Abstract

N-heterocyclic carbene (NHC)–gold and –silver complexes have attracted the interest of the scientific community because of their multiple applications and their versatility in being chemically modified in order to improve their biological properties. However, most of these complexes contain one or more chiral centers, and have been obtained and studied as racemic mixture. In particular, concerning the interesting biological and medicinal properties, many questions about how the chirality may influence these properties still remain unanswered. Aiming at a better understanding, herein a series of enantiopure NHC–gold and –silver complexes was synthesized, characterized and biologically evaluated in different in vitro systems. The individuated complexes exerted different properties based on the complexed metal and the specific configuration, with the (R)-gold–NHC complexes being the most active, particularly as anti-inflammatory molecules. Docking simulations indicated a different binding mode for each enantiomer. Moreover, anticancer and antibacterial activities were also evaluated for the considered enantiomers. Overall, the reported data may contribute to a better understanding of the different biological properties exerted by the enantiopure gold and silver complexes. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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13 pages, 2812 KiB

Open AccessArticle

Synthesis and Structure of 5-Methyl-9-(trifluoromethyl)-12H-quino[3,4-b][1,4]benzothiazinium Chloride as Anticancer Agent

by Andrzej Zieba, Violetta Kozik, Kinga Suwinska, Agata Kawulok, Tadeusz Pluta, Josef Jampilek and Andrzej Bak

Molecules 2024, 29(18), 4337; https://doi.org/10.3390/molecules29184337 - 12 Sep 2024

Viewed by 669

Abstract

In this work, the synthesis, structural analysis and anticancer properties of 5-methyl-9-trifluoromethyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (3) are described. Compound 3 was synthesized by reacting 1-methyl-4-butylthio-3-(benzoylthio)quinolinium chloride with 4-(trifluoromethyl)aniline, respectively. The structure of the resulting product was determined using ¹H-NMR and ¹³C-NMR spectroscopy as well as HR-MS spectrometry. The spatial geometry of agent 3 and the arrangement of molecules in the crystal (unit cell) were also confirmed using X-ray diffraction. The tetracyclic quinobenzothiazinium system is fairly planar because the dihedral angle between the planes formed by the benzene ring and the quinoline system is 173.47°. In order to obtain insight into the electronic charge distribution of the investigated molecule, electronic structure calculations employing the Density Functional Theory (DFT) were performed. Moreover, antiproliferative activity against a set of pancreatic cancer cell lines was tested, with compound 3 showing IC₅₀ values against human primary pancreatic adenocarcinoma BxPC-3 and human epithelioid pancreatic carcinoma Panc-1 of 0.051 µM and 0.066 µM, respectively. The IC₅₀ value of cytotoxicity/cell viability of the investigated compound assessed on normal human lung fibroblasts WI38 was 0.36 µM. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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14 pages, 2012 KiB

Open AccessArticle

Free Radical Production Induced by Nitroimidazole Compounds Lead to Cell Death in Leishmania infantum Amastigotes

by Julia Andrés-Rodríguez, María-Cristina González-Montero, Nerea García-Fernández, Estefanía Calvo-Álvarez, María-Yolanda Pérez-Pertejo, Rosa-María Reguera-Torres, Rafael Balaña-Fouce and Carlos García-Estrada

Molecules 2024, 29(17), 4041; https://doi.org/10.3390/molecules29174041 - 26 Aug 2024

Viewed by 780

Abstract

Leishmania infantum is the vector-borne trypanosomatid parasite causing visceral leishmaniasis in the Mediterranean basin. This neglected tropical disease is treated with a limited number of obsolete drugs that are not exempt from adverse effects and whose overuse has promoted the emergence of resistant pathogens. In the search for novel antitrypanosomatid molecules that help overcome these drawbacks, drug repurposing has emerged as a good strategy. Nitroaromatic compounds have been found in drug discovery campaigns as promising antileishmanial molecules. Fexinidazole (recently introduced for the treatment of stages 1 and 2 of African trypanosomiasis), and pretomanid, which share the nitroimidazole nitroaromatic structure, have provided antileishmanial activity in different studies. In this work, we have tested the in vitro efficacy of these two nitroimidazoles to validate our 384-well high-throughput screening (HTS) platform consisting of L. infantum parasites emitting the near-infrared fluorescent protein (iRFP) as a biomarker of cell viability. These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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8 pages, 673 KiB

Open AccessArticle

Concise Synthesis of Pseudane IX, Its N-Oxide, and Novel Carboxamide Analogs with Antibacterial Activity

by Plamen Angelov, Yordanka Mollova-Sapundzhieva, Francisco Alonso, Bogdan Goranov, Paraskev Nedialkov and Denitsa Bachvarova

Molecules 2024, 29(15), 3676; https://doi.org/10.3390/molecules29153676 - 2 Aug 2024

Viewed by 833

Abstract

A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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14 pages, 4460 KiB

Open AccessArticle

Discovery of Dolutegravir Derivative against Liver Cancer via Inducing Autophagy and DNA Damage

by Xixi Hou, Dong Yan, Ziyuan Wu, Longfei Mao, Huili Wang, Yajie Guo and Jianxue Yang

Molecules 2024, 29(8), 1779; https://doi.org/10.3390/molecules29081779 - 13 Apr 2024

Viewed by 1680

Abstract

We introduced a terminal alkyne into the core structure of dolutegravir, resulting in the synthesis of 34 novel dolutegravir-1,2,3-triazole compounds through click chemistry. These compounds exhibited remarkable inhibitory activities against two hepatocellular carcinoma cell lines, Huh7 and HepG2. Notably, compounds 5e and 5p demonstrated exceptional efficacy, particularly against Huh7 cells, with IC₅₀ values of 2.64 and 5.42 μM. Additionally, both compounds induced apoptosis in Huh7 cells, suppressed tumor cell clone formation, and elevated reactive oxygen species (ROS) levels, further promoting tumor cell apoptosis. Furthermore, compounds 5e and 5p activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound 5e exhibited low toxicity, highlighting its potential as a promising anti-tumor drug. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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20 pages, 4940 KiB

Open AccessArticle

Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives

by Eman S. M. Elsenbawy, Zafer S. Alshehri, Nouf A. Babteen, Adel A.-H. Abdel-Rahman, Mai A. El-Manawaty, Eman S. Nossier, Reem K. Arafa and Nasser A. Hassan

Molecules 2024, 29(5), 1067; https://doi.org/10.3390/molecules29051067 - 29 Feb 2024

Cited by 1 | Viewed by 1465

Abstract

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, β-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC₅₀ = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC₅₀ = 40.0 ± 3.9 μM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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16 pages, 1863 KiB

Open AccessArticle

β-Nicotinamide Mononucleotide Promotes Cell Proliferation and Hair Growth by Reducing Oxidative Stress

by Chuntao Xu, Jiawei Dai, Hongxia Ai, Weian Du and Hongbing Ji

Molecules 2024, 29(4), 798; https://doi.org/10.3390/molecules29040798 - 8 Feb 2024

Cited by 2 | Viewed by 5517

Abstract

β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer’s disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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14 pages, 1209 KiB

Open AccessArticle

5-Nitrofuran-Tagged Oxazolyl Pyrazolopiperidines: Synthesis and Activity against ESKAPE Pathogens

by Elizaveta Rogacheva, Lyudmila Kraeva, Alexey Lukin, Lyubov Vinogradova, Kristina Komarova, Mikhail Chudinov, Maxim Gureev and Evgeny Chupakhin

Molecules 2023, 28(18), 6491; https://doi.org/10.3390/molecules28186491 - 7 Sep 2023

Cited by 2 | Viewed by 1157

Abstract

A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPPs) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of the ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (13g), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure–activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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21 pages, 2559 KiB

Open AccessArticle

A New Way to 2,3,4-Trisubstituted Benzo[h]quinolines: Synthesis, Consecutive Reactions and Cellular Activities †

by Viktor A. Zapol’skii, Sandra Kaul, Bianka Karge, Mark Brönstrup, Mimoza Gjikaj and Dieter E. Kaufmann

Molecules 2023, 28(6), 2479; https://doi.org/10.3390/molecules28062479 - 8 Mar 2023

Viewed by 1648

Abstract

The reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene provides the appropriate precursors for the synthesis of 2,3,4-trisubstituted benzo[h]quinolines. These heterocycles are easily accessible via a single-step reaction with naphthalen-1-amine or anthracen-1-amine as the precursor. Due to the steric bulk and high electron density ring, the ring closure of benzo[h]quinolines takes place exclusively. Such highly substituted annelated pyridine systems can be modified in subsequent, selective reactions to build up new N-heterocycles with promising microbiological properties. The antibacterial and antiproliferative assays against four mammalian cell lines demonstrate that some of the sulfur-substituted benzo[h]quinoline analogs display potent phenotypic bioactivities in the single-digit micromolar range. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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13 pages, 2910 KiB

Open AccessArticle

Construction of 5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles via the One-Pot Reaction of Alkyl Isocyanides with Aryl/Alkyl Carbonyl Chlorides and Diaminomaleonitrile: Fluorescence and Antimicrobial Activity Evaluation

by Amal Al-Azmi and Elizabeth John

Molecules 2022, 27(23), 8278; https://doi.org/10.3390/molecules27238278 - 27 Nov 2022

Viewed by 1568

Abstract

5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles were successfully synthesized in good to moderate yields by reacting alkyl isocyanides with aryl/alkyl carbonyl chlorides, followed by the addition of diaminomaleonitrile. The synthesized pyrazines were fully characterized in this investigation, and X-ray crystal structure analysis was performed on some derivatives. The antibacterial and antifungal activities of the newly synthesized pyrazine-2,3-dicarbonitriles were assessed in addition to their UV and fluorescence results. All the compounds showed similar UV–Vis spectral features with absorption peaks (λ_max) around 267, 303, and 373 nm. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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14 pages, 1682 KiB

Open AccessArticle

Synthesis of Homodrimane Sesquiterpenoids Bearing 1,3-Benzothiazole Unit and Their Antimicrobial Activity Evaluation

by Lidia Lungu, Caleria Cucicova, Svetlana Blaja, Alexandru Ciocarlan, Ion Dragalin, Alic Barba, Nicoleta Vornicu, Elisabeta-Irina Geana, Ionel I. Mangalagiu and Aculina Aricu

Molecules 2022, 27(16), 5082; https://doi.org/10.3390/molecules27165082 - 10 Aug 2022

Cited by 3 | Viewed by 1699

Abstract

Based on some homodrimane carboxylic acids and their acyl chlorides, a series of fourteen 2-homodrimenyl-1,3-benzothiazoles, N-homodrimenoyl-2-amino-1,3-benzothiazoles, 4′-methyl-homodrimenoyl anilides and 4′-methyl-homodrimenthioyl anilides were synthesized and their biological activities were evaluated on five species of fungi (Aspergillus niger, Fusarium solani, Penicillium chrysogenum, P. frequentans, and Alternaria alternata) and two strains of bacteria (Bacillus sp. and Pseudomonas aeruginosa). The synthesis involved the decarboxylative cyclization, condensation and thionation of the said acids, anhydrides or their derivatives with 2-aminothiophenol, 2-aminobenzothiazole, p-toluidine and Lawesson’s reagent. As a result, together with the desired compounds, some unexpected products 8, 25, and 27 were obtained, and the structures and mechanisms for their formation have been proposed. Compounds 4, 9, and 25 showed higher antifungal and antibacterial activity compared to the standards caspofungin (MIC = 1.5 μg/mL) and kanamycin (MIC = 3.0 μg/mL), while compound 8 had comparable activities. In addition, compounds 6, 17, and 27 showed selective antifungal activity at MIC = 2.0, 0.25, and 1.0 μg/mL, respectively. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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Review

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67 pages, 5953 KiB

Open AccessReview

N-Heterocycles as Promising Antiviral Agents: A Comprehensive Overview

by Gulraiz Ahmad, Maria Sohail, Muhammad Bilal, Nasir Rasool, Muhammad Usman Qamar, Codrut Ciurea, Luigi Geo Marceanu and Catalin Misarca

Molecules 2024, 29(10), 2232; https://doi.org/10.3390/molecules29102232 - 10 May 2024

Cited by 3 | Viewed by 2486

Abstract

Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host’s immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects. Full article

(This article belongs to the Special Issue Chemistry and Health: Nitrogen Heterocycle Chemistry and Medicinal Chemistry)

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