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Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications
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Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications

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

Deadline for manuscript submissions: 31 March 2025 | Viewed by 11593

Special Issue Editors

Prof. Dr. Maria Novella Romanelli

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Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child’s Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Interests: enzyme modulators; ion channel modulators; multi-target ligands; antihyperalgesic agents; receptor modulators
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Silvia Dei

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child’s Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Interests: anticancer drugs; PGP modulators; antibacterials; multitarget-ligands; receptor modulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to several statistical analyses, a high percentage of drugs or biologically-active compounds contain aliphatic or aromatic heterocycles. Such moieties can be an essential part of the pharmacophore (antifungal azoles are an example) or may be used to modify ADME/TOX properties (for instance, piperazines in kinase inhibitors). Heterocycles can be used in drug design following optimization strategies such as bioisosterism or scaffold-hopping; in particular, nitrogen-containing heterocycles can be introduced to provide basic or H-bond forming groups to improve both the pharmacological and pharmaceutical profiles of the drug candidate. Owing to such wide application, the published synthetic methods are continuously applied and optimized to obtain new derivatives, and new synthetic methods are constantly developed in order to overcome the limitations of the existing procedures. In recent times, it has been also possible to obtain heterocycles containing elements largely ignored in medicinal chemistry such as silicon, selenium, phosphorous or boron, and, in some cases, to obtain drugs, such as vaborbactam, a beta-lactamase inhibitor that has been approved for therapy.

Prof. Dr. Maria Novella Romanelli
Prof. Dr. Silvia Dei
Guest Editors

Manuscript Submission Information

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Keywords

  • medicinal chemistry
  • heterocycles
  • organic synthesis
  • natural products
  • pharmacophore
  • artificial intelligence
  • CNS drugs
  • antibacterial agents
  • antiviral drugs
  • anticancer agents
  • enzyme modulators
  • receptor modulators
  • ion channel modulators

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Published Papers (6 papers)

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Research

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32 pages, 3339 KiB  
Article
Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold
by Laura Braconi, Chiara Riganti, Astrid Parenti, Marta Cecchi, Alessio Nocentini, Gianluca Bartolucci, Marta Menicatti, Marialessandra Contino, Nicola Antonio Colabufo, Dina Manetti, Maria Novella Romanelli, Claudiu T. Supuran and Elisabetta Teodori
Molecules 2024, 29(14), 3290; https://doi.org/10.3390/molecules29143290 - 11 Jul 2024
Viewed by 1587
Abstract
A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and [...] Read more.
A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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18 pages, 3402 KiB  
Article
Synthesis of 2-Ethylhexyl 5-Bromothiophene-2-Carboxylates; Antibacterial Activities against Salmonella Typhi, Validation via Docking Studies, Pharmacokinetics, and Structural Features Determination through DFT
by Waseem Nazeer, Muhammad Usman Qamar, Nasir Rasool, Mohamed Taibi and Ahmad Mohammad Salamatullah
Molecules 2024, 29(13), 3005; https://doi.org/10.3390/molecules29133005 - 25 Jun 2024
Cited by 1 | Viewed by 871
Abstract
A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A–4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The [...] Read more.
A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A–4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The results indicated that the majority of compounds showed promising effective in vitro antibacterial activity. Herein, 2-ethylhexyl-5-(p-tolyl)thiophene-2-carboxylate (4F), in particular among the synthesized analogs, showed outstanding antibacterial action (MIC value 3.125 mg/mL) against XDR Salmonella Typhi compared to ciprofloxacin and ceftriaxone. The intermolecular interaction was investigated by using a molecular docking study of thiophene derivatives 4A–4G against XDR S. Typhi. The values of the binding affinity of functionalized thiophene molecules and ciprofloxacin were compared against bacterial enzyme PDB ID: 5ztj. Therefore, 4F appears to be a promising antibacterial agent and showed the highest potential value. Density functional theory (DFT) calculations were executed to examine the electronic, structural, and spectroscopic features of the newly synthesized molecules 4A–4G. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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Review

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23 pages, 6915 KiB  
Review
Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors—Synthetic Strategies and SAR Insights
by Amol T. Mahajan, Shivani, Ashok Kumar Datusalia, Carmine Coluccini, Paolo Coghi and Sandeep Chaudhary
Molecules 2024, 29(15), 3560; https://doi.org/10.3390/molecules29153560 - 29 Jul 2024
Cited by 1 | Viewed by 1504
Abstract
Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their [...] Read more.
Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure–activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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52 pages, 22828 KiB  
Review
Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents
by Elisabetta Barresi, Emma Baglini, Valeria Poggetti, Jacopo Castagnoli, Doralice Giorgini, Silvia Salerno, Sabrina Taliani and Federico Da Settimo
Molecules 2024, 29(9), 2127; https://doi.org/10.3390/molecules29092127 - 3 May 2024
Cited by 4 | Viewed by 2525
Abstract
Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) [...] Read more.
Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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24 pages, 11879 KiB  
Review
Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids
by Rui Peng, Mengwei Xu, Baocheng Xie, Qing Min, Siwen Hui, Ziwei Du, Yan Liu, Wei Yu, Shi Wang, Xin Chen, Guang Yang, Zhaofang Bai, Xiaohe Xiao and Shuanglin Qin
Molecules 2023, 28(18), 6588; https://doi.org/10.3390/molecules28186588 - 13 Sep 2023
Cited by 6 | Viewed by 2412
Abstract
Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer [...] Read more.
Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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33 pages, 4554 KiB  
Review
Nortopsentins as Leads from Marine Organisms for Anticancer and Anti-Inflammatory Agent Development
by Camilla Pecoraro, Francesca Terrana, Giovanna Panzeca, Barbara Parrino, Stella Cascioferro, Patrizia Diana, Elisa Giovannetti and Daniela Carbone
Molecules 2023, 28(18), 6450; https://doi.org/10.3390/molecules28186450 - 5 Sep 2023
Cited by 4 | Viewed by 1929
Abstract
The marine environment is an excellent source of molecules that have a wide structural diversity and a variety of biological activities. Many marine natural products (MNPs) have been established as leads for anticancer drug discovery. Most of these compounds are alkaloids, including several [...] Read more.
The marine environment is an excellent source of molecules that have a wide structural diversity and a variety of biological activities. Many marine natural products (MNPs) have been established as leads for anticancer drug discovery. Most of these compounds are alkaloids, including several chemical subclasses. In this review, we focus on the bis-indolyl alkaloid Nortopsentins and their derivatives with antiproliferative properties. Nortopsentins A–C were found to exhibit in vitro cytotoxicity against the P388 murine leukaemia cell line. Their structural manipulation provided a wide range of derivatives with significant anti-tumour activity against human cell lines derived from different cancer types (bladder, colon, gastric, CNS, liver, lung, breast, melanoma, ovarian, pancreatic, prostate, pleural mesothelioma, renal, sarcoma, and uterus). In vivo assays on animal models also proved that Nortopsentins and related bis-indolyl compounds have potent anti-inflammatory activity. These remarks set the foundation for future investigations into the development of new Nortopsentin derivatives as new anticancer and anti-inflammatory agents. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)
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