Hybrid Isatin and Imatinib Analogues as Potential Antineoplastic Agents Andressa Paula de Oliveira, João de Mello Rezende Neto, Talita Alves Nunes da Silva, Pamela Gomes de Almeida, Luiz Cláudio Ferreira Pimentel, Stefany de Castro Bazan Moura, Rafael Ferreira Dantas, Floriano Silva‐Jr, Patrícia Dias Fernandes, Tácio Vinício Amorim Fernandes, Monica Macedo Bastos, Nubia Boechat Archiv Der Pharmazie, 2026 Cancer is a multifactorial disease often linked to genetic mutations that disrupt protein tyrosine kinases (PTKs) and signaling pathways such as PI3K/Akt/mTOR, driving malignancies such as chronic myeloid leukemia (CML), prostate carcinoma, glioblastoma, and gastrointestinal stromal tumors (GISTs). Tyrosine kinase inhibitors (TKIs), including imatinib and sunitinib, have revolutionized cancer therapy by selectively targeting kinases such as Bcr‐Abl1 (CML) and KIT/PDGFRα (GIST), offering substantial clinical benefits. Motivated by their success, 15 hybrid derivatives ( 4a–e , 5a–e , 6a–e ) based on the isatin–phenylaminopyrimidine pyridine (PAPP) scaffold were designed, synthesized, and evaluated in cell lines with dysregulated tyrosine kinase activity. Among them, compounds 6b and 6e showed promising cytotoxicity against the K562 cell line (Bcr‐Abl1), with CC₅₀ values of 8.7 and 12.2 μM, though they also affected WSS‐1 cells, suggesting limited tumor selectivity. Compound 4c displayed strong cytotoxic activity against several solid tumor cell lines, including DU145 (3.9 μM), MCF7 (3.5 μM), HT29 (7.7 μM), NCI‐H1299 (19.5 μM), and T98G (9.0 μM). Importantly, all tested compounds showed low erythrocytic toxicity (CC₅₀ > 30 μM).
Discovery of [1,2,4]triazolo[1,5-a]pyrimidine-Imatinib Hybrids With Selective Cytotoxic Activity: A Mechanistically Divergent Series From Direct BCR-ABL1 Inhibition Stefany Castro Bazan Moura, Andressa Paula de Oliveira, Joao de Mello Rezende Neto, Rafael Ferreira Dantas, Floriano Paes Silva‐Jr, Luiz Claudio Pimentel, Mayara Salles do Nascimento Carvalho, Debora Inacio Leite, Daiane Vitoria da Silva, Monica Macedo Bastos, Nubia Boechat Chemmedchem, 2026 Chronic myeloid leukemia treatment faces the challenge of resistance to BCR‐ABL1 tyrosine kinase inhibitors. To address this, we rationally designed six new imatinib‐derived compounds 2(a–f) by replacing the quinoline moiety with a [1,2,4]triazolo[1,5‐ a ]pyrimidine scaffold via classical bioisosterism. The compounds were efficiently synthesized and characterized. Biological evaluation revealed that compound 2a exhibited cytotoxic activity in BCR‐ABL1‐positive K562 cells (47% viability inhibition at 10 µM, IC 50 = 9.7 µM). However, enzymatic assays demonstrated that 2a does not directly inhibit the wild‐type ABL1 kinase, unlike IMT. This finding, coupled with its cytotoxicity in nontumorigenic WSS‐1 cells, indicates an alternative, off‐target mechanism. A clear structure–activity relationship identified the detrimental effect of a ‐CF 3 substitution. Overall, this work applies bioisosteric replacement to generate a new chemotype and uncovers a mechanistically divergent lead. The distinct, ABL1‐independent mechanism of compound 2a establishes a solid foundation for future optimization and highlights its potential as a starting point for developing novel antimyeloproliferative agents with a different therapeutic profile.
A Review on Medicinal Chemistry and Biological Activity of Dihydropyrimidinones Against HIV Debora I. Leite, Fernando B. Macedo, Murilo Marinho de C. Lima, Isabelle S. Brum, Jonathan Fragoso Miranda de Oliveira, Ana Clara S. Costa, Stella C. Duarte, Sarah Moon, Stefany de Castro B. Moura, Andressa P. de Oliveira, Nubia Boechat, Monica M. Bastos Archiv Der Pharmazie, 2026 Dihydropyrimidinones (DHPMs), also referred to as pyrimidinones, are privileged structures widely employed in the search for new compounds capable of inhibiting HIV replication. This core is found in natural alkaloids isolated from marine sponge species, which are known to inhibit the binding of the viral surface protein gp120 to the CD4 receptor of target cells. In addition, DHPMs exhibit a close structural relationship with nucleic acids, macromolecules that constitute the genetic material of both living organisms and viruses. Furthermore, the DHPM nucleus is present in several important anti‐HIV drugs that inhibit reverse transcriptase and integrase enzymes, indicating that the use of these privileged structures represents a faster and more promising approach for the development of novel HIV inhibitors. In this review, we provide an overview of DHPM‐based compounds as potential future trends in AIDS treatment, with a focus on studies published over the last 10 years. Overall, our analysis indicates that compounds containing the DHPM core generally display high potency against multiple HIV targets and may overcome antiviral resistance, reinforcing the relevance of this pharmacophoric fragment for the development of effective and innovative antiretroviral therapies.
The activity, selectivity and pharmacological profile of imatinib derivates against Trypanosoma cruzi Luca Salles Fonseca Nesic de Freitas, Denise da Gama Jaèn Batista, Cristiane França da Silva, Marcos Meuser Batista, Liviane D. de Azevedo, Luiz Claudio Ferreira Pimentel, Monica Macedo Bastos, Nubia Boechat, Maria de Nazaré Correia Soeiro Parasitology, 2026 Abstract Chagas disease (CD) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi affecting more than 6 million people worldwide. Its treatment is based in old and toxic nitroderivative drugs necessitating for new alternatives. Imatinib (IMB) is a tyrosine kinase inhibitor used in cancer therapy, and previous reports demonstrate that some derivatives are active against T. cruzi justifying further synthesis screening of novel compounds derived from IMB. Our results demonstrate that all test derivatives are highly active against the intracellular forms of T. cruzi being similar or even more potent than the reference drug for CD – benznidazole (BZ). Besides, they were much more active than the parent molecule, displaying low EC 90 values (<10 µ m ) and good selectivity indexes (>10), which are relevant characteristics of a novel hit compound for CD therapy. However, when screened against bloodstream trypomastigotes, only 1 derivative, named PLDC 23/19, was as active (EC 50 = 18.8 µ m ) as BZ (EC 50 = 18.8 µ m ), while the others did not show activity up to 20 µ m .
Comparative Effectiveness of Daily Oral and Long-acting Injectable Prep: A Critical Review of Clinical Evidence and Public Health Implications Ariel F. T. Croner, Debora I. Leite, Isabelle S. Brum, Maria da Conceição A. Dias, Luiz Claudio F. Pimentel, Monica M. Bastos, Nubia Boechat Current HIV Research, 2025 The Human Immunodeficiency Virus (HIV) is the cause of Acquired Immunodefi-ciency Syndrome (AIDS). Preexposure Prophylaxis (PrEP) antiretroviral drugs to prevent HIV-1 infection are currently available in many countries. In Brazil, the recommended and approved regimen for PrEP is a daily Fixed-Dose Combination (FDC) tablet of Tenofovir Disoproxil Fumarate (TDF) with Emtricitabine (FTC) (300/200 mg), marketed as Truvada®. However, ad-herence to daily oral pill regimens remains one of the greatest challenges for the successful use of PrEP. Therefore, a Long-Acting Injectable (LAI) PrEP regimen, such as Cabotegravir (CAB), could significantly improve adherence to prophylaxis. The aim of this study was to compare the use of PrEP with TDF+FTC and the long-acting injectable cabotegravir, as well as to examine the mechanisms of action of the drugs involved in PrEP. In fact, the results confirmed the safety and efficacy of the use of CAB as an LAI PrEP. In June 2025, the FDA approved the use of LEN for PrEP, and it is expected that other regulatory agencies will follow suit by the end of the year. Emerging strategies under development include annual LEN formulations, the use of broadly Neutralizing Antibodies (bNAbs), and the Dapivirine Vaginal Ring (DPV), which has demon-strated greater convenience and improved adherence among pregnant women compared to oral PrEP. Additionally, digital monitoring tools are being explored, although their effectiveness relies on the implementation of equitable health policies. Thus, integrated prevention models that com-bine biomedical innovations with community-based interventions emerge as essential to expand-ing the reach and impact of PrEP.
Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development Mayara Nascimento, Stefany Moura, Lidia Parra, Valeska Vasconcellos, Gabriela Costa, Debora Leite, Maria Dias, Tácio Vinício Amorim Fernandes, Lucas Hoelz, Luiz Pimentel, Monica Bastos, Nubia Boechat Pharmaceuticals, 2024 The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
Spirooxadiazoline-oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells Liviane D. de Azevedo, Debora I. Leite, Andressa P. de Oliveira, Floriano P. S. Junior, Rafael F. Dantas, Monica M. Bastos, Nubia Boechat, Luiz C. F. Pimentel Archiv Der Pharmazie, 2024 Imatinib mesylate was the first representative BCR‐ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR‐ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR‐ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS‐1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino‐pyrimidine‐pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro‐oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8–9.8 µM.
New azaaurone derivatives as potential multitarget agents in HIV-TB coinfection Debora I. Leite, Andre Campaniço, Pedro A. G. Costa, Isadora A. Correa, Luciana J. da Costa, Monica M. Bastos, Rui Moreira, Francisca Lopes, Audrey Jordaan, Digby F. Warner, Nubia Boechat Archiv Der Pharmazie, 2024 Tuberculosis (TB) disease, caused by Mycobacterium tuberculosis (Mtb) is the leading cause of death among people with human immunodeficiency virus (HIV) infection. No dual‐target drug is currently being used to simultaneously treat both infections. This work aimed to obtain new multitarget HIV‐TB agents, with the goal of optimizing treatments and preventing this coinfection. These compounds incorporate the structural features of azaaurones as anti‐Mtb and zidovudine (AZT) as the antiretroviral moiety. The azaaurone scaffold displayed submicromolar activities against Mtb, and AZT is a potent antiretroviral drug. Six derivatives were synthetically generated, and five were evaluated against both infective agents. Evaluations of anti‐HIV activity were carried out in HIV‐1‐infected MT‐4 cells and on endogenous HIV‐1 reverse transcriptase (RT) activity. The H37Rv strain was used for anti‐Mtb assessments. Most compounds displayed potent antitubercular and moderate anti‐HIV activity. (E)‐12 exhibited a promising multitarget profile with an MIC90 of 2.82 µM and an IC50 of 1.98 µM in HIV‐1‐infected T lymphocyte cells, with an 84% inhibition of RT activity. Therefore, (E)‐12 could be the first promising compound from a family of multitarget agents used to treat HIV‐TB coinfection. In addition, the compound could offer a prototype for the development of new strategies in scientific research to treat this global health issue.
Alternative Reactions to Friedel-crafts Acylation on Highly Activated Substrates Debora Inacio Leite, Luiz Claudio Ferreira Pimentel, Maria da Conceição Avelino Dias, Monica Macedo Bastos, Nubia Boechat Current Organic Chemistry, 2024 Friedel-crafts acylation (FCAcyl) is the most widespread method used to prepare aryl ketones and aldehydes. However, depending on the type of group attached to the benzene, their derivatives influence the electronic characteristics and structural orientations of the compounds during acylation; thus, the groups are very important for the success of the reaction. The existence of strong electron-donating groups, such as polyhydroxy/ polyalkoxyphenols and anilines on the aromatic ring, makes this reaction difficult. To overcome these problems and with the aim of obtaining aromatic ketones from benzene compounds, appropriate methodologies were described. Therefore, this review consists of showing the importance and applicability of the Houben-Hoesch and Sugasawa reactions as alternatives for the Friedel-crafts acylation of polyhydroxy/polyalkoxyphenols and anilines, respectively. The main advances used in the original methodologies were also described. The use of these reactions as an alternative to the renowned Friedel-crafts acylation reactions should be taken into consideration as an important synthetic tool because there is the possibility of reducing steps, with consequent improvement of yield, in addition to optimizing reaction performance.
Antiplasmodial, Trypanocidal, and Genotoxicity In Vitro Assessment of New Hybrid α,α-Difluorophenylacetamide-statin Derivatives Carlos Fernando Araujo-Lima, Rita de Cassia Castro Carvalho, Sandra Loureiro Rosario, Debora Inacio Leite, Anna Caroline Campos Aguiar, Lizandra Vitoria de Souza Santos, Julianna Siciliano de Araujo, Kelly Salomão, Carlos Roland Kaiser, Antoniana Ursine Krettli, Monica Macedo Bastos, Claudia Alessandra Fortes Aiub, Maria de Nazaré Correia Soeiro, Nubia Boechat, Israel Felzenszwalb Pharmaceuticals, 2023
A Review of the Development of Multitarget Molecules against HIV-TB Coinfection Pathogens Debora Inacio Leite, Stefany de Castro Bazan Moura, Maria da Conceição Avelino Dias, Carolina Catta Preta Costa, Gustavo Peixoto Machado, Luiz Claudio Ferreira Pimentel, Frederico Silva Castelo Branco, Rui Moreira, Monica Macedo Bastos, Nubia Boechat Molecules, 2023
In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19 Carolina Q Sacramento, Natalia Fintelman-Rodrigues, Jairo R Temerozo, Aline de Paula Dias Da Silva, Suelen da Silva Gomes Dias, Carine dos Santos da Silva, André C Ferreira, Mayara Mattos, Camila R R Pão, Caroline S de Freitas, Vinicius Cardoso Soares, Lucas Villas Bôas Hoelz, Tácio Vinício Amorim Fernandes, Frederico Silva Castelo Branco, Mônica Macedo Bastos, Núbia Boechat, Felipe B Saraiva, Marcelo Alves Ferreira, Steffen Jockusch, Xuanting Wang, Chuanjuan Tao, Minchen Chien, Wei Xie, Dinshaw Patel, Aitor Garzia, Thomas Tuschl, James J Russo, Rajith K R Rajoli, Carolina S G Pedrosa, Gabriela Vitória, Letícia R Q Souza, Livia Goto-Silva, Marilia Zaluar Guimarães, Stevens K Rehen, Andrew Owen, Fernando A Bozza, Dumith Chequer Bou-Habib, Jingyue Ju, Patrícia T Bozza, Thiago Moreno L Souza Journal of Antimicrobial Chemotherapy, 2021
Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication André C. Ferreira, Patrícia A. Reis, Caroline S. de Freitas, Carolina Q. Sacramento, Lucas Villas Bôas Hoelz, Mônica M. Bastos, Mayara Mattos, Natasha Rocha, Isaclaudia Gomes de Azevedo Quintanilha, Carolina da Silva Gouveia Pedrosa, Leticia Rocha Quintino Souza, Erick Correia Loiola, Pablo Trindade, Yasmine Rangel Vieira, Giselle Barbosa-Lima, Hugo C. de Castro Faria Neto, Nubia Boechat, Stevens K. Rehen, Karin Brüning, Fernando A. Bozza, Patrícia T. Bozza, Thiago Moreno L. Souza Antimicrobial Agents and Chemotherapy, 2019
Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo Caroline S. de Freitas, Luiza M. Higa, Carolina Q. Sacramento, André C. Ferreira, Patrícia A. Reis, Rodrigo Delvecchio, Fabio L. Monteiro, Giselle Barbosa-Lima, Harrison James Westgarth, Yasmine Rangel Vieira, Mayara Mattos, Natasha Rocha, Lucas Villas Bôas Hoelz, Rennan Papaleo Paes Leme, Mônica M. Bastos, Gisele Olinto L. Rodrigues, Carla Elizabeth M. Lopes, Celso Martins Queiroz-Junior, Cristiano X. Lima, Vivian V. Costa, Mauro M. Teixeira, Fernando A. Bozza, Patrícia T. Bozza, Nubia Boechat, Amilcar Tanuri, Thiago Moreno L. Souza Plos Neglected Tropical Diseases, 2019
New 1,2,3-triazole-based analogues of benznidazole for use against Trypanosoma cruzi infection: In vitro and in vivo evaluations Débora Inácio Leite, Fábio de Vasconcellos Fontes, Monica Macedo Bastos, Lucas Villas Boas Hoelz, Maria da Conceição Avelino Dias Bianco, Andressa Paula de Oliveira, Patricia Bernardino da Silva, Cristiane França da Silva, Denise da Gama Jean Batista, Aline Nefertiti Silva da Gama, Raiza Brandão Peres, Jose Daniel Figueroa Villar, Maria de Nazaré Correia Soeiro, Nubia Boechat Chemical Biology and Drug Design, 2018
Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia Liviane D. Azevedo, Mônica M. Bastos, Flávia C. Vasconcelos, Lucas V. B. Hoelz, Floriano P. S. Junior, Rafael F. Dantas, Ana C. M. de Almeida, Andressa Paula de Oliveira, Larissa C. Gomes, Raquel C. Maia, Nubia Boechat Medicinal Chemistry Research, 2017
Corrigendum: The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication Carolina Q. Sacramento, Gabrielle R. de Melo, Caroline S. de Freitas, Natasha Rocha, Lucas Villas Bôas Hoelz, Milene Miranda, Natalia Fintelman-Rodrigues, Andressa Marttorelli, André C. Ferreira, Giselle Barbosa-Lima, Juliana L. Abrantes, Yasmine Rangel Vieira, Mônica M. Bastos, Eduardo de Mello Volotão, Estevão Portela Nunes, Diogo A. Tschoeke, Luciana Leomil, Erick Correia Loiola, Pablo Trindade, Stevens K. Rehen, Fernando A. Bozza, Patrícia T. Bozza, Nubia Boechat, Fabiano L. Thompson, Ana M. B. de Filippis, Karin Brüning, Thiago Moreno L. Souza Scientific Reports, 2017
The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication Carolina Q. Sacramento, Gabrielle R. de Melo, Caroline S. de Freitas, Natasha Rocha, Lucas Villas Bôas Hoelz, Milene Miranda, Natalia Fintelman-Rodrigues, Andressa Marttorelli, André C. Ferreira, Giselle Barbosa-Lima, Juliana L. Abrantes, Yasmine Rangel Vieira, Mônica M. Bastos, Eduardo de Mello Volotão, Estevão Portela Nunes, Diogo A. Tschoeke, Luciana Leomil, Erick Correia Loiola, Pablo Trindade, Stevens K. Rehen, Fernando A. Bozza, Patrícia T. Bozza, Nubia Boechat, Fabiano L. Thompson, Ana M. B. de Filippis, Karin Brüning, Thiago Moreno L. Souza Scientific Reports, 2017
Tenofovir: Structure-activity relationship and synthetic methods Débora I. Leite, Jéssica V. Faria, Liviane D. de Azevedo, Yasmin V. Figueiredo, Wagner Alexandre Martins, Maria da Conceição A. D. Bianco, Alice Maria R. Bernardino, Mônica M. Bastos, Núbia Boechat Revista Virtual De Quimica, 2015
New trifluoromethyl triazolopyrimidines as Anti-Plasmodium falciparum agents Núbia Boechat, Luiz C. S. Pinheiro, Thiago S. Silva, Anna C. C. Aguiar, Alcione S. Carvalho, Monica M. Bastos, Carolina C. P. Costa, Sergio Pinheiro, Angelo C. Pinto, Jorge S. Mendonça, Karen D. B. Dutra, Alessandra L. Valverde, Osvaldo A. Santos-Filho, Isabela P. Ceravolo, Antoniana U. Krettli Molecules, 2012
[1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl]methanol hemihydrate Nübia Boechat, Maria de Lourdes G. Ferreira, Monica M. Bastos, James L. Wardell, Solange M. S. V. Wardell, Edward R. T. Tiekink Acta Crystallographica Section E Structure Reports Online, 2011
Novel 1,2,3-triazole derivatives for use against mycobacterium tuberculosis H37Rv (ATCC 27294) strain Nubia Boechat, Vitor F. Ferreira, Sabrina B. Ferreira, Maria de Lourdes G. Ferreira, Fernando de C. da Silva, Monica M. Bastos, Marilia dos S. Costa, Maria Cristina S. Lourenço, Angelo C. Pinto, Antoniana U. Krettli, Anna Caroline Aguiar, Brunno M. Teixeira, Nathalia V. da Silva, Priscila R. C. Martins, Flavio Augusto F. M. Bezerra, Ane Louise S. Camilo, Gerson P. da Silva, Carolina C. P. Costa Journal of Medicinal Chemistry, 2011
