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Drug Discovery: Design, Synthesis and Activity Evaluation
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Drug Discovery: Design, Synthesis and Activity Evaluation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 5547

Special Issue Editors

Dr. Joana L. C. Sousa

E-Mail Website
Guest Editor
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: heterocyclic compounds
Prof. Dr. Artur M. S. Silva

E-Mail Website
Guest Editor
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: organic chemistry; green synthetic organic chemistry; synthesis of heterocyclic compounds; natural products; NMR techniques; synthesis of new compounds with biocidal and antioxidant activities
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue “Drug Discovery: Design, Synthesis and Activity Evaluation” aims at publishing studies within the medicinal chemistry field. In particular, it intends to cover the early stage of preclinical research in the drug discovery pipeline, including target identification and validation; hit discovery; assay development and screening; high-throughput screening; hit to lead; lead optimization; in vivo, in vitro and ex vivo assays; absorption, distribution, metabolism, and excretion (ADME); and drug delivery. Moreover, it welcomes not only original research papers, but also comprehensive reviews.

The original research papers should comprise the design (with or without computational support), organic synthesis, characterization, and biological activity evaluation of novel potent lead compounds, considering small to large biologically active molecules.

Dr. Joana L. C. Sousa
Prof. Dr. Artur M. S. Silva
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • drug design
  • organic synthesis
  • biological activity evaluation
  • biologically active compounds
  • diagnostic/therapeutic agents
  • labeled ligands
  • structure–activity relationships (SARs)
  • structural biological studies
  • computational studies
  • pharmacokinetics/pharmacodynamics
  • drug delivery

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Published Papers (4 papers)

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29 pages, 24011 KiB  
Article
In Silico and In Vivo Evaluation of Novel 2-Aminobenzothiazole Derivative Compounds as Antidiabetic Agents
by Juan Andres Alvarado Salazar, Miguel Valdes, Alejandro Cruz, Brenda Moreno de Jesús, David Patiño González, Ivonne María Olivares Corichi, Feliciano Tamay Cach and Jessica Elena Mendieta Wejebe
Int. J. Mol. Sci. 2025, 26(3), 909; https://doi.org/10.3390/ijms26030909 - 22 Jan 2025
Viewed by 995
Abstract
Currently, there are several drugs used for the treatment of type 2 diabetes (T2D); however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two [...] Read more.
Currently, there are several drugs used for the treatment of type 2 diabetes (T2D); however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two series of 2-aminobenzothiazole derivatives linked to isothioureas (3a–w) or guanidines (4a–z) for the treatment of T2D. The ADMET properties were determined in silico, from which it was possible to select nine compounds (two isothioureas and seven guanidines), and, with molecular docking, it was shown that compounds methyl (E)-N′-(benzo[d]thiazol-2-yl)-N-methylcarbamimidothioate (3b) and 2-(benzo[d]thiazol-2-yl)-1,3-di-tert-butylguanidine (4y) showed a high affinity for PPARγ (ΔG = −7.8 and −8.4 kcal/mol, respectively). In vivo, the LD50 value was estimated in rats based on OECD Guideline 425, being >1750 mg/kg for both compounds. The pharmacological effect of 3b and 4y was evaluated in the T2D rat model, showing that after oral administration in an equimolar ratio to pioglitazone (15 mg/kg) for 4 weeks, both compounds were able to reduce blood glucose levels (<200 mg/dL) and improve the lipid profile. Therefore, 3b and 4y could be used in the future as antidiabetic agents. Full article
(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)
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16 pages, 1626 KiB  
Article
Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis
by Tamás Pálla, Károly Mazák, Dania Mohammed Alkhazragee, György Tibor Balogh, Béla Noszál and Arash Mirzahosseini
Int. J. Mol. Sci. 2024, 25(23), 12727; https://doi.org/10.3390/ijms252312727 - 27 Nov 2024
Viewed by 917
Abstract
The accurate determination of acid/base constants (proton dissociation constants—pKa, or equivalently protonation constants—logK) is essential for the physicochemical characterization of new molecules, especially in drug design and development, as these parameters thoroughly influence the pharmacokinetics and pharmacodynamics of [...] Read more.
The accurate determination of acid/base constants (proton dissociation constants—pKa, or equivalently protonation constants—logK) is essential for the physicochemical characterization of new molecules, especially in drug design and development, as these parameters thoroughly influence the pharmacokinetics and pharmacodynamics of drug action. While pH/potentiometric titration remains the gold standard method for determining acid/base constants, spectroscopic techniques—particularly nuclear magnetic resonance spectroscopy (as NMR/pH titrations)—have emerged as powerful alternatives for specific challenges in analytical chemistry, providing also information on the structure and site of protonation. In this study, we performed a comprehensive meta-analysis of protonation constants reported in the literature, measured using both potentiometry and NMR titrations. Our analysis compiled the available literature data and assessed the agreement between the two methods, taking into consideration various experimental conditions, such as temperature and ionic strength. The results provide insights into the reliability and applicability of NMR titrations compared with potentiometry, offering guidance for selecting appropriate methodologies in drug design. Full article
(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)
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29 pages, 5961 KiB  
Article
Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors
by Iván Díaz, Sofía Salido, Manuel Nogueras and Justo Cobo
Int. J. Mol. Sci. 2024, 25(17), 9744; https://doi.org/10.3390/ijms25179744 - 9 Sep 2024
Cited by 2 | Viewed by 1232
Abstract
The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family [...] Read more.
The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13–18)(a–d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7–12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a–d)) under microwave irradiation at 150–170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 μM. Additionally, all compounds with IC50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 μM, and the other thirteen behaving as double inhibitors. Full article
(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)
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15 pages, 4622 KiB  
Article
Computational Design of Novel Cyclic Peptides Endowed with Autophagy-Inhibiting Activity on Cancer Cell Lines
by Marco Albani, Enrico Mario Alessandro Fassi, Roberta Manuela Moretti, Mariangela Garofalo, Marina Montagnani Marelli, Gabriella Roda, Jacopo Sgrignani, Andrea Cavalli and Giovanni Grazioso
Int. J. Mol. Sci. 2024, 25(9), 4622; https://doi.org/10.3390/ijms25094622 - 24 Apr 2024
Cited by 1 | Viewed by 1675
Abstract
(1) Autophagy plays a significant role in development and cell proliferation. This process is mainly accomplished by the LC3 protein, which, after maturation, builds the nascent autophagosomes. The inhibition of LC3 maturation results in the interference of autophagy activation. (2) In this study, [...] Read more.
(1) Autophagy plays a significant role in development and cell proliferation. This process is mainly accomplished by the LC3 protein, which, after maturation, builds the nascent autophagosomes. The inhibition of LC3 maturation results in the interference of autophagy activation. (2) In this study, starting from the structure of a known LC3B binder (LIR2-RavZ peptide), we identified new LC3B ligands by applying an in silico drug design strategy. The most promising peptides were synthesized, biophysically assayed, and biologically evaluated to ascertain their potential antiproliferative activity on five humans cell lines. (3) A cyclic peptide (named Pep6), endowed with high conformational stability (due to the presence of a disulfide bridge), displayed a Kd value on LC3B in the nanomolar range. Assays accomplished on PC3, MCF-7, and A549 cancer cell lines proved that Pep6 exhibited cytotoxic effects comparable to those of the peptide LIR2-RavZ, a reference LC3B ligand. Furthermore, it was ineffective on both normal prostatic epithelium PNT2 and autophagy-defective prostate cancer DU145 cells. (4) Pep6 can be considered a new autophagy inhibitor that can be employed as a pharmacological tool or even as a template for the rational design of new small molecules endowed with autophagy inhibitory activity. Full article
(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)
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