Nitrogen Containing Scaffolds in Medicinal Chemistry

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

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 23086

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Department of Pharmaceutical Chemistry and drug Technology \"Sapienza\", University of Rome, Rome, Italy
Interests: drug design; synthesis of new potential bioactive compounds in the field of anticancer, antiviral and antiparasitic agents; structure–activity relationship study; organic synthesis
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Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy
Interests: drug design; synthesis of new potential bioactive compounds in the field of anticancer; antiviral and antiparasitic agents; structure–activity relationship study; organic synthesis
Special Issues, Collections and Topics in MDPI journals

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Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, 89081 Ulm, Germany
Interests: analytical chemistry; mass spectrometry; natural products; phytochemistry; bioactivity; cancer; inflammation

Special Issue Information

Dear Colleagues,

Most of the organic compounds used as pharmaceuticals or intermediates utilized for their synthesis contain heterocyclic motifs. Heterocycle is a ring with at least one atom that is not carbon. Nitrogen, oxygen, and sulfur are the primary elements seen in common heterocycles, which play a critical role in drug discovery. Nitrogen-containing scaffolds are among the most significant structural components of pharmaceuticals. Notably, there are also natural products, dyes and others in which the common element turns out to be the nitrogen atom.

In detail, nitrogen heterocycles contain at least one nitrogen atom in the ring. Based on the size of the ring, there are three, four, five, six, seven and eight-membered rings, as well as fused, bicyclic and macrocyclic heterocycles of nitrogen. Furthermore, they are grouped as aromatic, saturated or unsaturated.

Depending on the structure and on the type of bonds, such compounds show different acid-base properties and they can contain one, two or more nitrogen atoms.

Over the past decades, much attention has been devoted to the development and pharmacology of heteroaromatic organic compounds (such as benzimidazoles, benzothiazoles, indole, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines) that are currently considered privileged scaffolds for different pharmaceuticals. Indeed they show a wide range of biological activities, representing nearly 60% of all FDA-approved drugs. The number of N-heterocycle drugs approved by the US FDA is more than 880. In particular, nitrogen-based heterocyclic compounds are widely reported in the literature as antitumor agents and represent 73% of the approved anticancer drugs in 2015. This Special Issue will acknowledge research papers with topics including, but not limited to, the preparation of aromatic and non-aromatic nitrogen-containing heterocycles endowed with any biological action. Contributions that highlight the importance of nitrogen-based scaffolds that are widely found in: agrochemicals, dyes, cosmetics and functional materials are also welcome. The aim of the present review is also an overview primarily of the state of the art of synthetic methods and recent advances in the synthesis of nitrogen heterocycles.

Dr. Antonella Messore
Dr. Valentina Noemi Madia
Dr. Michael Schmiech
Guest Editors

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Keywords

  • nitrogen heterocycles
  • biological activity
  • target-based design
  • structure-activity relationship
  • docking studies
  • ADMET
  • organocatalysis
  • photocatalysis
  • microwave-assisted synthesis
  • green chemistry
  • one-pot multicomponent reactions

Published Papers (9 papers)

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Research

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17 pages, 3037 KiB  
Article
Antibacterial Properties and Computational Insights of Potent Novel Linezolid-Based Oxazolidinones
by M. Shaheer Malik, Shaikh Faazil, Meshari A. Alsharif, Qazi Mohammad Sajid Jamal, Jabir H. Al-Fahemi, Amrita Banerjee, Arpita Chattopadhyay, Samir Kumar Pal, Ahmed Kamal and Saleh A. Ahmed
Pharmaceuticals 2023, 16(4), 516; https://doi.org/10.3390/ph16040516 - 30 Mar 2023
Cited by 2 | Viewed by 1557
Abstract
The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial [...] Read more.
The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial potential of the novel oxazolidinone-sulphonamide/amide conjugates that were recently reported by our research group. The antibacterial assays showed that, from the series, oxazolidinones 2 and 3a exhibited excellent potency (MIC of 1.17 μg/mL) against B. subtilis and P. aeruginosa strains, along with good antibiofilm activity. Docking studies revealed higher binding affinities of oxazolidinones 2 and 3a compared to linezolid, which were further validated by molecular dynamics simulations. In addition to this, other computational studies, one-descriptor (log P) analysis, ADME-T and drug likeness studies demonstrated the potential of these novel linezolid-based oxazolidinones to be taken forward for further studies. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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13 pages, 2289 KiB  
Article
Novel Indole-Tethered Chromene Derivatives: Synthesis, Cytotoxic Properties, and Key Computational Insights
by M. Shaheer Malik, Hissana Ather, Shaik Mohammad Asif Ansari, Ayesha Siddiqua, Qazi Mohammad Sajid Jamal, Ali H. Alharbi, Munirah M. Al-Rooqi, Rabab S. Jassas, Essam M. Hussein, Ziad Moussa, Rami J. Obaid and Saleh A. Ahmed
Pharmaceuticals 2023, 16(3), 333; https://doi.org/10.3390/ph16030333 - 22 Feb 2023
Cited by 2 | Viewed by 1653
Abstract
Indole-tethered chromene derivatives were synthesised in a one-pot multicomponent reaction using N-alkyl-1H-indole-3-carbaldehydes, 5,5-dimethylcyclohexane-1,3-dione, and malononitrile, catalysed by DBU at 60–65 °C in a short reaction time. The benefits of the methodology include non-toxicity, an uncomplicated set-up procedure, a faster reaction [...] Read more.
Indole-tethered chromene derivatives were synthesised in a one-pot multicomponent reaction using N-alkyl-1H-indole-3-carbaldehydes, 5,5-dimethylcyclohexane-1,3-dione, and malononitrile, catalysed by DBU at 60–65 °C in a short reaction time. The benefits of the methodology include non-toxicity, an uncomplicated set-up procedure, a faster reaction time, and high yields. Moreover, the anticancer properties of the synthesised compounds were tested against selected cancer cell lines. The derivatives 4c and 4d displayed very good cytotoxic activity, with IC50 values ranging from 7.9 to 9.1 µM. Molecular docking revealed the potent derivatives have good binding affinity towards tubulin protein, better than the control, and the molecular dynamic simulations further demonstrated the stability of ligand-receptor interactions. Moreover, the derivatives followed all the drug-likeness filters. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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18 pages, 4270 KiB  
Article
Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line
by Naheed Akhter, Sidra Batool, Samreen Gul Khan, Nasir Rasool, Fozia Anjum, Azhar Rasul, Şevki Adem, Sadaf Mahmood, Aziz ur Rehman, Mehr un Nisa, Zainib Razzaq, Jørn B. Christensen, Mohammed A. S. Abourehab, Syed Adnan Ali Shah and Syahrul Imran
Pharmaceuticals 2023, 16(2), 211; https://doi.org/10.3390/ph16020211 - 30 Jan 2023
Cited by 5 | Viewed by 2084
Abstract
Triazole-based acetamides serve as important scaffolds for various pharmacologically active drugs. In the present work, structural hybrids of 1,2,4-triazole and acetamides were furnished by chemically modifying 2-(4-isobutylphenyl) propanoic acid (1). Target compounds 7a–f were produced in considerable yields (70–76%) by coupling [...] Read more.
Triazole-based acetamides serve as important scaffolds for various pharmacologically active drugs. In the present work, structural hybrids of 1,2,4-triazole and acetamides were furnished by chemically modifying 2-(4-isobutylphenyl) propanoic acid (1). Target compounds 7a–f were produced in considerable yields (70–76%) by coupling the triazole of compound 1 with different electrophiles under different reaction conditions. These triazole-coupled acetamide derivatives were verified by physiochemical and spectroscopic (HRMS, FTIR, 13CNMR, and 1HNMR,) methods. The anti-liver carcinoma effects of all of the derivatives against a HepG2 cell line were investigated. Compound 7f, with two methyl moieties at the ortho-position, exhibited the highest anti-proliferative activity among all of the compounds with an IC50 value of 16.782 µg/mL. 7f, the most effective anti-cancer molecule, also had a very low toxicity of 1.190.02%. Molecular docking demonstrates that all of the compounds, especially 7f, have exhibited excellent binding affinities of −176.749 kcal/mol and −170.066 kcal/mol to c-kit tyrosine kinase and protein kinase B, respectively. Compound 7f is recognized as the most suitable drug pharmacophore for the treatment of hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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12 pages, 1540 KiB  
Article
Pyrrolyl and Indolyl α-γ-Diketo Acid Derivatives Acting as Selective Inhibitors of Human Carbonic Anhydrases IX and XII
by Davide Ialongo, Antonella Messore, Valentina Noemi Madia, Valeria Tudino, Alessio Nocentini, Paola Gratteri, Simone Giovannuzzi, Claudiu T. Supuran, Alice Nicolai, Susanna Scarpa, Samanta Taurone, Michele Camarda, Marco Artico, Veronica Papa, Francesco Saccoliti, Luigi Scipione, Roberto Di Santo and Roberta Costi
Pharmaceuticals 2023, 16(2), 188; https://doi.org/10.3390/ph16020188 - 27 Jan 2023
Cited by 1 | Viewed by 1895
Abstract
Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid/base regulation, carbonic anhydrases (CAs) are involved in several physiological/pathological [...] Read more.
Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid/base regulation, carbonic anhydrases (CAs) are involved in several physiological/pathological processes, including tumors. Indeed, CAs are clinically relevant in cancer therapy as among the fifteen human isoforms, two of them, namely CA IX (overexpressed in solid tumors and associated with increased metastasis and poor prognosis) and CA XII (overexpressed in some tumors) are involved in tumorigenesis. Targeting these two isoforms is considered as a pertinent approach to develop new cancer therapeutics. Several CA inhibitors (CAIs) have been described, even though they are unselective inhibitors of different isoforms. Thus, efforts are needed to find new selective CAIs. In this work, we described new diketo acid derivatives as CAIs, with the best acting compounds 1c and 5 as nanomolar inhibitors of CA IX and XII, being also two orders of magnitude selective over CAs I and II. Molecular modeling studies showed the different binding poses of the best acting CAIs within CA II and IX, highlighting the key structural features that could confer the ability to establish specific interactions within the enzymes. In different tumor cell lines overexpressing CA IX and XII, the tested compounds showed antiproliferative activity already at 24 h treatment, with no effects on somatic not transformed cells. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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18 pages, 3692 KiB  
Article
New Insights into the Structural Requirements of Isatin-Derived Pro-Apoptotic Agents against Acute Myeloid Leukemia
by Ahmed K. Hamdy, Takashi Sakamoto, Tsugumasa Toma, Masaharu Sakamoto, Mohammed A. S. Abourehab, Masami Otsuka, Mikako Fujita, Hiroshi Tateishi and Mohamed O. Radwan
Pharmaceuticals 2022, 15(12), 1579; https://doi.org/10.3390/ph15121579 - 17 Dec 2022
Cited by 2 | Viewed by 2218
Abstract
Searching for bioactive compounds within the huge chemical space is like trying to find a needle in a haystack. Isatin is a unique natural compound which is endowed with different bio-pertinent activities, especially in cancer therapy. Herein, we envisaged that adopting a hybrid [...] Read more.
Searching for bioactive compounds within the huge chemical space is like trying to find a needle in a haystack. Isatin is a unique natural compound which is endowed with different bio-pertinent activities, especially in cancer therapy. Herein, we envisaged that adopting a hybrid strategy of isatin and α,β-unsaturated ketone would afford new chemical entities with strong chemotherapeutic potential. Of interest, compounds 5b and 5g demonstrated significant antiproliferative activities against different cancer genotypes according to NCI-60 screening. Concomitantly, their IC50 against HL-60 cells were 0.38 ± 0.08 and 0.57 ± 0.05 µM, respectively, demonstrating remarkable apoptosis and moderate cell cycle arrest at G1 phase. Intriguingly, an impressive safety profile for 5b was reflected by a 37.2 times selectivity against HL-60 over PBMC from a healthy donor. This provoked us to further explore their mechanism of action by in vitro and in silico tools. Conclusively, 5b and 5g stand out as strong chemotherapeutic agents that hold clinical promise against acute myeloid leukemia. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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14 pages, 1587 KiB  
Article
Biotransformation of Modified Benzylisoquinoline Alkaloids: Boldine and Berberine and In Silico Molecular Docking Studies of Metabolites on Telomerase and Human Protein Tyrosine Phosphatase 1B
by Duaa Eliwa, Abdel-Rahim S. Ibrahim, Amal Kabbash, Mona El-Aasr, Michał Tomczyk, Yousef A. Bin Jardan, Gaber El-Saber Batiha and Amany E. Ragab
Pharmaceuticals 2022, 15(10), 1195; https://doi.org/10.3390/ph15101195 - 28 Sep 2022
Cited by 4 | Viewed by 1657
Abstract
Natural nitrogen heterocycles biotransformation has been extensively used to prepare synthetic drugs and explore the fate of therapeutic agents inside the body. Herein, the ability of filamentous fungi to biotransform boldine and berberine was investigated. Docking simulation studies of boldine, berberine and their [...] Read more.
Natural nitrogen heterocycles biotransformation has been extensively used to prepare synthetic drugs and explore the fate of therapeutic agents inside the body. Herein, the ability of filamentous fungi to biotransform boldine and berberine was investigated. Docking simulation studies of boldine, berberine and their metabolites on the target enzymes: telomerase (TERT) and human protein tyrosine phosphatase 1B (PTP-1B) were also performed to investigate the anticancer and antidiabetic potentials of compounds in silico. The biotransformation of boldine and berberine with Cunninghamella elegans NRRL 2310, Rhodotorula rubra NRRL y1592, Penicillium chrysogeneum ATCC 10002, Cunninghamella blackesleeana MR198 and Cunninghamella blackesleeana NRRL 1369 via demethylation, N- oxidation, glucosidation, oxidation and hydroxylation reactions produced seven metabolites, namely: 1,10-didesmethyl-boldine (1), laurolitsine (2), 1,10-didesmethyl-norboldine (3), boldine-9-O-β-D-glucoside (4), tridesmethyl berberine (5), demethylene berberine (6), and lambertine (7). Primarily, the structures of the metabolites were established by one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses and mass spectrometry. In silico molecular docking simulation of the metabolites of boldine and berberine to the proteins TERT and PTP-1B, respectively, revealed good binding MolDock scores comparable to boldine and berberine and favorable interactions with the catalytic sites of the proteins. In conclusion, this study presented promising biologically prepared nitrogen scaffolds (isoquinolines) of boldine and berberine. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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21 pages, 3633 KiB  
Article
Bio-Oriented Synthesis of Novel (S)-Flurbiprofen Clubbed Hydrazone Schiff’s Bases for Diabetic Management: In Vitro and In Silico Studies
by Aftab Alam, Mumtaz Ali, Najeeb Ur Rehman, Saeed Ullah, Sobia Ahsan Halim, Abdul Latif, Zainab, Ajmal Khan, Obaid Ullah, Shujaat Ahmad, Ahmed Al-Harrasi and Manzoor Ahmad
Pharmaceuticals 2022, 15(6), 672; https://doi.org/10.3390/ph15060672 - 27 May 2022
Cited by 35 | Viewed by 2218
Abstract
A new series of (S)-flurbiprofen derivatives 4a4p and 5a5n were synthesized with different aromatic or aliphatic aldehydes and ketones to produce Schiff’s bases and their structures were confirmed through HR-ESI-MS, 1H, and 13C-NMR spectroscopy. The α-glucosidase inhibitory [...] Read more.
A new series of (S)-flurbiprofen derivatives 4a4p and 5a5n were synthesized with different aromatic or aliphatic aldehydes and ketones to produce Schiff’s bases and their structures were confirmed through HR-ESI-MS, 1H, and 13C-NMR spectroscopy. The α-glucosidase inhibitory activities of the newly synthesized compounds were scrutinized, in which six compounds 5k, 4h, 5h, 4d, 4b, and 5i showed potent inhibition in the range of 0.93 to 10.26 µM, respectively, whereas fifteen compounds 4c, 4g, 4i, 4j, 4l, 4m, 4o, 4p, 5c, 5d, 5j, 5l, 5m, 5n and 1 exhibited significant inhibitory activity with IC50 in range of = 11.42 to 48.39 µM. In addition, compounds 5g, 5f, 4k, 4n, and 4f displayed moderate-to-low activities. The modes of binding of all the active compounds were determined through the molecular docking approach, which revealed that two residues, specifically Glu277 and His351 are important in the stabilization of the active compounds in the active site of α-glucosidase. Furthermore, these compounds block the active site with high binding energies (−7.51 to −3.36 kcal/mol) thereby inhibiting the function of the enzyme. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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11 pages, 1206 KiB  
Article
Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity
by Mohamed Zaki, Mohammed Loubidi, Tuğçe Bilgiç, Derviş Birim, Mohamed Akssira, Taner Dagcı, Sabine Berteina-Raboin, Luciano Saso, Mostafa Khouili and Güliz Armagan
Pharmaceuticals 2022, 15(4), 421; https://doi.org/10.3390/ph15040421 - 30 Mar 2022
Viewed by 1739
Abstract
N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole [...] Read more.
N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the α-methylene-γ-butyrolactone function, while the 1,2,3-triazolo-tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN3) and the α-methylene-γ-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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Review

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68 pages, 12431 KiB  
Review
Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective
by Adarsh Kumar, Ankit Kumar Singh, Harshwardhan Singh, Veena Vijayan, Deepak Kumar, Jashwanth Naik, Suresh Thareja, Jagat Pal Yadav, Prateek Pathak, Maria Grishina, Amita Verma, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas and Pradeep Kumar
Pharmaceuticals 2023, 16(2), 299; https://doi.org/10.3390/ph16020299 - 14 Feb 2023
Cited by 40 | Viewed by 6588
Abstract
Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop [...] Read more.
Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)
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