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Pharmaceuticals
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10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022)
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10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022)

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 15037

Special Issue Editors

Prof. Dr. Carlos Alberto Manssour Fraga

E-Mail Website
Guest Editor
1. Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
2. Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
Interests: medicinal chemistry; drug design and discovery; multitarget drugs for neurodegenerative diseases; use of privileged structures to design new epigenetic drug candidates; discovery of new kinase inhibitors for chronic inflammatory diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Arthur Eugen Kümmerle

E-Mail Website
Guest Editor
LaDMol-QM (Molecular Diversity and Medicinal Chemistry Laboratory), Departament of Organic Chemistry, Federal Rural University of Rio de Janeiro (UFRRJ), Seropédica, RJ, Brazil
Interests: Alzheimer; cancer; inflammation; multi-target compounds; theranostics; medicinal chemistry; organic synthesis
Dr. Hugo Verli

E-Mail Website
Guest Editor
Structural Bioinformatics Group, Department of Molecular Biology and Biotechnology, Institute of Biosciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Interests: molecular modeling; molecular dynamics; docking; molecular recognition; SAR; molecular structure; molecular conformation

Special Issue Information

Dear Colleagues,

Back in 2001, when the first Brazilian Symposium on Medicinal Chemistry (BrazMedChem) was organized, we could never have imagined that it would become the largest scientific event exclusively dedicated to Medicinal Chemistry in Latin America. During the last twenty years, its various organizers have excelled in the design of multidisciplinary scientific programs that cover the most diverse disciplines and areas that constitute the mosaic of research in medicinal chemistry and complex chain of drug discovery and development. The presence of thousands of young and senior researchers around the world has been the registered trade of BrazMedChem, ensuring a friendly interactive and collaborative atmosphere, aiming to discuss the state of the art of medicinal chemistry and how our work and perspectives can help science to overcome all current challenges related to collective health and effective advances in pharmaceutical sciences and drug discovery.

BrazMedChem 2022 participants are cordially invited to contribute original research papers or reviews to this Special Issue of Pharmaceuticals. Other regular submissions are also cordially encouraged to this issue.

Prof. Dr. Carlos Alberto Manssour Fraga
Dr. Arthur Eugen Kümmerle
Dr. Hugo Verli
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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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

  • medicinal chemistry
  • drug design
  • drug discovery
  • drug development
  • molecular modeling
  • organic synthesis
  • pharmacological evaluation
  • drug targets
  • drugs for neglected diseases
  • drug candidates

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

21 pages, 4273 KiB  
Article
Piperine–Chlorogenic Acid Hybrid Inhibits the Proliferation of the SK-MEL-147 Melanoma Cells by Modulating Mitotic Kinases
by Carolina Girotto Pressete, Flávia Pereira Dias Viegas, Thâmara Gaspar Campos, Ester Siqueira Caixeta, João Adolfo Costa Hanemann, Guilherme Álvaro Ferreira-Silva, Bruno Zavan, Alexandre Ferro Aissa, Marta Miyazawa, Claudio Viegas, Jr. and Marisa Ionta
Pharmaceuticals 2023, 16(2), 145; https://doi.org/10.3390/ph16020145 - 19 Jan 2023
Cited by 10 | Viewed by 2595
Abstract
Melanoma is considered the most aggressive form of skin cancer, showing high metastatic potential and persistent high mortality rates despite the introduction of immunotherapy and targeted therapies. Thus, it is important to identify new drug candidates for melanoma. The design of hybrid molecules, [...] Read more.
Melanoma is considered the most aggressive form of skin cancer, showing high metastatic potential and persistent high mortality rates despite the introduction of immunotherapy and targeted therapies. Thus, it is important to identify new drug candidates for melanoma. The design of hybrid molecules, with different pharmacophore fragments combined in the same scaffold, is an interesting strategy for obtaining new multi-target and more effective anticancer drugs. We designed nine hybrid compounds bearing piperine and chlorogenic acid pharmacophoric groups and evaluated their antitumoral potential on melanoma cells with distinct mutational profiles SK-MEL-147, CHL-1 and WM1366. We identified the compound named PQM-277 (3a) to be the most cytotoxic one, inhibiting mitosis progression and promoting an accumulation of cells in pro-metaphase and metaphase by altering the expression of genes that govern G2/M transition and mitosis onset. Compound 3a downregulated FOXM1, CCNB1, CDK1, AURKA, AURKB, and PLK1, and upregulated CDKN1A. Molecular docking showed that 3a could interact with the CUL1-RBX1 complex, which activity is necessary to trigger molecular events essential for FOXM1 transactivation and, in turn, G2/M gene expression. In addition, compound 3a effectively induced apoptosis by increasing BAX/BCL2 ratio. Our findings demonstrate that 3a is an important antitumor candidate prototype and support further investigations to evaluate its potential for melanoma treatment, especially for refractory cases to BRAF/MEK inhibitors. Full article
(This article belongs to the Special Issue 10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022))
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16 pages, 2382 KiB  
Article
Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies
by Raquel B. M. de Almeida, Deyse B. Barbosa, Mayra R. do Bomfim, Jéssika A. O. Amparo, Bruno S. Andrade, Silvia L. Costa, Joaquín M. Campos, Jorddy N. Cruz, Cleydson B. R. Santos, Franco H. A. Leite and Mariana B. Botura
Pharmaceuticals 2023, 16(1), 95; https://doi.org/10.3390/ph16010095 - 9 Jan 2023
Cited by 34 | Viewed by 3897
Abstract
The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer’s disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases [...] Read more.
The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer’s disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC50 = 543.8 µM) and against BuChE (IC50 = 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors. Full article
(This article belongs to the Special Issue 10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022))
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17 pages, 1913 KiB  
Article
2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties
by Daniela R. de Oliveira, Rodolfo C. Maia, Patrícia R. de Carvalho França, Patrícia D. Fernandes, Gisele Barbosa, Lídia M. Lima and Carlos A. Manssour Fraga
Pharmaceuticals 2022, 15(12), 1519; https://doi.org/10.3390/ph15121519 - 6 Dec 2022
Cited by 2 | Viewed by 1891
Abstract
Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7 [...] Read more.
Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7–11) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50–80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by N-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB1- or CB2-transfected cells, compounds demonstrated an inverse agonist profile on CB2 receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB2 receptor (Ki = 16 µM) with an EC50 = 0.36 µM (Emax = 63%). LASSBio-2265 (11) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases. Full article
(This article belongs to the Special Issue 10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022))
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26 pages, 2981 KiB  
Article
Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives
by Gleyton Sousa, Maria C. F. de Almeida, Lucas L. Lócio, Vanda L. dos Santos, Daniel P. Bezerra, Valdenizia R. Silva, Sinara M. V. de Almeida, Alice Simon, Thiago da S. Honório, Lucio M. Cabral, Rosane N. Castro, Ricardo O. de Moura and Arthur E. Kümmerle
Pharmaceuticals 2022, 15(9), 1098; https://doi.org/10.3390/ph15091098 - 2 Sep 2022
Cited by 10 | Viewed by 2879
Abstract
In this study, we report the synthesis of twenty new acridine–thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means [...] Read more.
In this study, we report the synthesis of twenty new acridine–thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M−1; Ksv = 2.6 × 103 M−1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM. Full article
(This article belongs to the Special Issue 10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022))
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22 pages, 3933 KiB  
Article
Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs
by Gisele Barbosa, Luis Gabriel Valdivieso Gelves, Caroline Marques Xavier Costa, Lucas Silva Franco, João Alberto Lins de Lima, Cristiane Aparecida-Silva, John Douglas Teixeira, Claudia dos Santos Mermelstein, Eliezer J. Barreiro and Lidia Moreira Lima
Pharmaceuticals 2022, 15(8), 913; https://doi.org/10.3390/ph15080913 - 23 Jul 2022
Cited by 6 | Viewed by 2114
Abstract
Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, [...] Read more.
Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives. Full article
(This article belongs to the Special Issue 10th Brazilian Symposium on Medicinal Chemistry (BrazMedChem_2022))
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