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Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential
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Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 21870

Special Issue Editors

Prof. Dr. Mohamed Jawed Ahsan

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari, Jaipur, Rajasthan 303 039, India
Interests: anticancer; antitubercular; green synthesis; medicinal chemistry; molecular docking; oxadiazoles; pyrazolines; pyrazoles
Special Issues, Collections and Topics in MDPI journals
Dr. Faizul Azam

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Uniazah 51911, Saudi Arabia
Interests: computational chemistry; molecular docking; molecular dynamics; DFT calculations
Special Issues, Collections and Topics in MDPI journals
Dr. Md. Afroz Bakht

E-Mail Website
Guest Editor
Department of Chemistry, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, P.O. Box- 83, Al-Kharj 11942, Saudi Arabia
Interests: catalysts; green synthesis; organic synthesis; nanoparticles; ultrasonic synthesis; ultrasonic extraction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Five and six-membered heterocyclic compounds are appealing targets found in a wide range of drug structures and have piqued the interest of medicinal chemists worldwide.

Many heterocyclic scaffolds can be considered as privilege structures. Nitrogen, oxygen, and sulphur are the most common heteroatoms found in heterocyclic compounds. According to statistics, a heterocycle is present in more than 85% of all biologically active chemical entities. Five-member heterocycles are classified as imidazoles, oxadiazoles, pyrazoles, thiadiazoles, triazoles, tetrazoles, and others depending on the number, nature, and arrangement of heteroatoms. They are important structural units in many pharmaceutical drugs. They can be found as an isolated ring or as a fused ring (e.g., benzimidazole, benzisoxazole, etc.). Similarly, six-membered heterocycles are classified as pyridine, pyrazine, dioxane, pyrimidine etc.

The oxadiazole ring can be found in drugs such as prenoxdiazine (cough suppressant), raltegravir (anti-HIV), and others, while pyrazoles heterocyle can be found in many NSAIDs (such as phenylbutazone, celecoxib, and others), antigout (sulfinpyrazole), and antipyretics (Aminophenazone). The thiadiazole ring is found in acetazolamide, a diuretic and carbonic anhydrase inhibitor, and the imidazole ring is found in histamines, phenytoin, and other drugs. The six-membered pyridine (e.g. isoniazid) and pyrazine (e.g. pyrazinamide) rings are found in antitubercular drugs.

This thematic issue deals with:

  1. Therapeutic potentials (anticancer, antitubercular, antimicrobial, anti-inflammatory, antioxidant, antiviral, etc.) of five and six-membered heterocycles.
  2. Conventional, microwave assisted and ultrasound mediated synthesis of five and six-membered heterocycles.
  3. The novel catalytic syntheses of five and six-membered heterocycles.
  4. Solvent free and green synthesis of five and six-member heterocycles.
  5. In-silico, molecular docking, molecular dynamics, and computational studies of five and six-membered heterocycles.
  6. Spectral characterization and DFT (HOMO and LUMO) studies of five and six-membered heterocycles.
  7. Structural modification of natural isolates into their semi-synthetic analogues (five and six-membered heterocycles).

Thus, the current Special Issue aims to collect and present recent advances in conventional and green synthesis, as well as their therapeutic applications related to five and six-membered heterocyclic compounds (communications, full papers, and reviews).

Prof. Dr. Mohamed Jawed Ahsan
Dr. Faizul Azam
Dr. Md. Afroz Bakht
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • anti-Alzheimer
  • anticancer
  • antitubercular
  • catalysts
  • green synthesis
  • heterocyclic compounds
  • in-silico studies
  • molecular docking
  • molecular dynamics
  • oxadiazoles
  • organic synthesis
  • pyrazoles
  • pyridine
  • pyrimidine
  • solvent free synthesis
  • thiadiazoles
  • ultrasonic and microwave synthesis
  • nanoparticles

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Related Special Issue

Published Papers (7 papers)

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Research

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14 pages, 1230 KiB  
Article
Effective Synthesis of 4-Quinolones by Reductive Cyclization of 2′-Nitrochalcones Using Formic Acid as a CO Surrogate
by Francesco Ferretti, Manar Ahmed Fouad, Cecilia Abbo and Fabio Ragaini
Molecules 2023, 28(14), 5424; https://doi.org/10.3390/molecules28145424 - 15 Jul 2023
Cited by 6 | Viewed by 1595
Abstract
4-Quinolones are the structural elements of many pharmaceutically active compounds. Although several approaches are known for their synthesis, the introduction of an aryl ring in position 2 is problematic with most of them. The reductive cyclization of o-nitrochalcones by pressurized CO, catalyzed [...] Read more.
4-Quinolones are the structural elements of many pharmaceutically active compounds. Although several approaches are known for their synthesis, the introduction of an aryl ring in position 2 is problematic with most of them. The reductive cyclization of o-nitrochalcones by pressurized CO, catalyzed by ruthenium or palladium complexes, has been previously reported to be a viable synthetic strategy for this aim, but the need for pressurized CO lines and autoclaves has prevented its widespread use. In this paper, we describe the use of the formic acid/acetic anhydride mixture as a CO surrogate, which allows us to perform the reaction in a cheap and commercially available thick-walled glass tube without adding any gaseous reagent. The obtained yields are often high and compare favorably with those previously reported by the use of pressurized CO. The procedure was applied to a three-step synthesis from commercially available and cheap reagents of the alkaloid Graveoline. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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20 pages, 8496 KiB  
Article
Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking
by Tian-Meng Cui, Muhammad Altaf, Abdu Aldarhami, Abdulrahman S. Bazaid, Nizar H. Saeedi, Almohanad A. Alkayyal, Fahad M. Alshabrmi, Farman Ali, Mohammed Aladhadh, Muhammad Yasir Khan, Ahad Amer Alsaiari and Yue-Rong Ma
Molecules 2023, 28(8), 3634; https://doi.org/10.3390/molecules28083634 - 21 Apr 2023
Cited by 3 | Viewed by 2253
Abstract
Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, [...] Read more.
Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1–40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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9 pages, 1317 KiB  
Article
Understanding the Regioselectivity and the Molecular Mechanism of [3 + 2] Cycloaddition Reactions between Nitrous Oxide and Conjugated Nitroalkenes: A DFT Computational Study
by Ewa Dresler, Aneta Wróblewska and Radomir Jasiński
Molecules 2022, 27(23), 8441; https://doi.org/10.3390/molecules27238441 - 2 Dec 2022
Cited by 8 | Viewed by 1532
Abstract
Regiochemical aspects and the molecular mechanism of the [3 + 2] cycloaddition between nitrous oxide and conjugated nitroalkenes were evaluated on the basis of the wb97xd/6-311 + G(d) (PCM) computational study. It was found that, independently of the nature of the nitroalkene, all [...] Read more.
Regiochemical aspects and the molecular mechanism of the [3 + 2] cycloaddition between nitrous oxide and conjugated nitroalkenes were evaluated on the basis of the wb97xd/6-311 + G(d) (PCM) computational study. It was found that, independently of the nature of the nitroalkene, all considered processes are realized via polar, single-step mechanisms. All attempts at the localization of hypothetical zwitterionic intermediates were unsuccessful. Additionally, the DFT computational study suggested that, in the course of the reaction, the formation of respective Δ2-4-nitro-4-R1-5-R2-1-oxa-2,3-diazolines was preferred from the kinetic point of view. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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13 pages, 2505 KiB  
Article
Small Heterocyclic Ligands as Anticancer Agents: QSAR with a Model G-Quadruplex
by Jose Kaneti, Vanya Kurteva, Milena Georgieva, Natalia Krasteva, George Miloshev, Nadezhda Tabakova, Zhanina Petkova and Snezhana M. Bakalova
Molecules 2022, 27(21), 7577; https://doi.org/10.3390/molecules27217577 - 4 Nov 2022
Cited by 5 | Viewed by 1948
Abstract
G-quadruplexes (GQs) have become valid targets for anticancer studies in recent decades due to their multifaceted biological function. Herewith, we aim to quantify interactions of potential heterocyclic ligands (Ls) with model GQs. For seven 4-aminoquinazolines and three 2-heteroaryl perimidines, seven of this ten-membered [...] Read more.
G-quadruplexes (GQs) have become valid targets for anticancer studies in recent decades due to their multifaceted biological function. Herewith, we aim to quantify interactions of potential heterocyclic ligands (Ls) with model GQs. For seven 4-aminoquinazolines and three 2-heteroaryl perimidines, seven of this ten-membered group so far unknown, we use routine quantum chemical modeling. As shown in the literature, a preferred mode of interaction of heterocycles with cellular structures is stacking to exposable faces of G-quadruplexes. To exploit the energy of this interaction as a molecular descriptor and achieve the necessary chemical precision, we use state of the art large-scale density functional theory (DFT) calculations of stacked heterocycles to a GQ. Actually, the GQ has been simplified for the computation by stripping it off all pentose phosphate residues into a naked model of stacked guanine quartets. The described model thus becomes computable. The obtained heterocyclic ligand GQ.L stacking energies, that is, their GQ affinities, are the necessary ligand descriptors. Using the ligand biological inhibitory activities (IC50) on a human malignant melanoma A375 cell line, we obtain a good linear relationship between computed ligand stacking affinities to GQ, and experimental log (IC50) values. Based on the latter relationship, we discuss a putative mechanism of anticancer activity of heterocyclic ligands via stacking interactions with GQs and thereby controlling cell regulatory activity. This mechanism may tentatively be applied to other condensed five- and six-membered small heterocycles as well. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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19 pages, 3492 KiB  
Article
Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes
by Sabbir Ahmed, Md Chayan Ali, Rumana Akter Ruma, Shafi Mahmud, Gobindo Kumar Paul, Md Abu Saleh, Mohammed Merae Alshahrani, Ahmad J. Obaidullah, Sudhangshu Kumar Biswas, Md Mafizur Rahman, Md Mizanur Rahman and Md Rezuanul Islam
Molecules 2022, 27(14), 4526; https://doi.org/10.3390/molecules27144526 - 15 Jul 2022
Cited by 28 | Viewed by 4979
Abstract
Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase [...] Read more.
Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = −45.02 kcal mol−1 for alpha-amylase and −38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of −36.796 kcal mol−1 for alpha-amylase and −29.622 kcal mol−1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors’ native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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28 pages, 13089 KiB  
Article
Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship
by Prangya Rath, Anuj Ranjan, Arabinda Ghosh, Abhishek Chauhan, Manisha Gurnani, Hardeep Singh Tuli, Hamza Habeeballah, Mustfa F. Alkhanani, Shafiul Haque, Kuldeep Dhama, Naval Kumar Verma and Tanu Jindal
Molecules 2022, 27(7), 2212; https://doi.org/10.3390/molecules27072212 - 29 Mar 2022
Cited by 8 | Viewed by 3223
Abstract
The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify [...] Read more.
The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure–activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R2 = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC50) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of −7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be −7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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Review

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40 pages, 4430 KiB  
Review
Thiazolidin-2,4-Dione Scaffold: An Insight into Recent Advances as Antimicrobial, Antioxidant, and Hypoglycemic Agents
by Harsh Kumar, Navidha Aggarwal, Minakshi Gupta Marwaha, Aakash Deep, Hitesh Chopra, Mohammed M. Matin, Arpita Roy, Talha Bin Emran, Yugal Kishore Mohanta, Ramzan Ahmed, Tapan Kumar Mohanta, Muthupandian Saravanan, Rakesh Kumar Marwaha and Ahmed Al-Harrasi
Molecules 2022, 27(19), 6763; https://doi.org/10.3390/molecules27196763 - 10 Oct 2022
Cited by 22 | Viewed by 3779
Abstract
Heterocyclic compounds containing nitrogen and sulfur, especially those in the thiazole family, have generated special interest in terms of their synthetic chemistry, which is attributable to their ubiquitous existence in pharmacologically dynamic natural products and also as overwhelmingly powerful agrochemicals and pharmaceuticals. The [...] Read more.
Heterocyclic compounds containing nitrogen and sulfur, especially those in the thiazole family, have generated special interest in terms of their synthetic chemistry, which is attributable to their ubiquitous existence in pharmacologically dynamic natural products and also as overwhelmingly powerful agrochemicals and pharmaceuticals. The thiazolidin-2,4-dione (TZD) moiety plays a central role in the biological functioning of several essential molecules. The availability of substitutions at the third and fifth positions of the Thiazolidin-2,4-dione (TZD) scaffold makes it a highly utilized and versatile moiety that exhibits a wide range of biological activities. TZD analogues exhibit their hypoglycemic activity by improving insulin resistance through PPAR-γ receptor activation, their antimicrobial action by inhibiting cytoplasmic Mur ligases, and their antioxidant action by scavenging reactive oxygen species (ROS). In this manuscript, an effort has been made to review the research on TZD derivatives as potential antimicrobial, antioxidant, and antihyperglycemic agents from the period from 2010 to the present date, along with their molecular mechanisms and the information on patents granted to TZD analogues. Full article
(This article belongs to the Special Issue Five and Six-Membered Heterocyclic Compounds and Their Therapeutic Potential)
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