Optimization of benzenesulfonyl derivatives as anti-Trypanosomatidae agents: Structural design, synthesis, and pharmacological assessment against Trypanosoma cruzi and Leishmania infantum
This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in t...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Guilherme Freitas de Lima Hercos Mariza Gabriela Faleiro de Moura Lodi Cruz Ana Clara Cassiano Martinho Daniela de Melo Resende Danilo Farago Nascimento Paula Derksen Macruz Eduardo Jorge Pilau Silvane Maria Fonseca Murta Celso de Oliveira Rezende J únio Source Type: research
Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds
Bioorg Med Chem. 2024 Apr 23;105:117734. doi: 10.1016/j.bmc.2024.117734. Online ahead of print.ABSTRACTAlthough cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of ...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Kristina Pavi ć Goran Poje Lais Pessanha de Carvalho Tana Tandari ć Marina Marinovi ć Diana Fontinha Jana Held Miguel Prud êncio Ivo Piantanida Robert Vianello Ivona Kro šl Knežević Ivana Perkovi ć Zrinka Raji ć Source Type: research
Optimization of benzenesulfonyl derivatives as anti-Trypanosomatidae agents: Structural design, synthesis, and pharmacological assessment against Trypanosoma cruzi and Leishmania infantum
This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in t...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Guilherme Freitas de Lima Hercos Mariza Gabriela Faleiro de Moura Lodi Cruz Ana Clara Cassiano Martinho Daniela de Melo Resende Danilo Farago Nascimento Paula Derksen Macruz Eduardo Jorge Pilau Silvane Maria Fonseca Murta Celso de Oliveira Rezende J únio Source Type: research
Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds
Bioorg Med Chem. 2024 Apr 23;105:117734. doi: 10.1016/j.bmc.2024.117734. Online ahead of print.ABSTRACTAlthough cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of ...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Kristina Pavi ć Goran Poje Lais Pessanha de Carvalho Tana Tandari ć Marina Marinovi ć Diana Fontinha Jana Held Miguel Prud êncio Ivo Piantanida Robert Vianello Ivona Kro šl Knežević Ivana Perkovi ć Zrinka Raji ć Source Type: research
Optimization of benzenesulfonyl derivatives as anti-Trypanosomatidae agents: Structural design, synthesis, and pharmacological assessment against Trypanosoma cruzi and Leishmania infantum
This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in t...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Guilherme Freitas de Lima Hercos Mariza Gabriela Faleiro de Moura Lodi Cruz Ana Clara Cassiano Martinho Daniela de Melo Resende Danilo Farago Nascimento Paula Derksen Macruz Eduardo Jorge Pilau Silvane Maria Fonseca Murta Celso de Oliveira Rezende J únio Source Type: research
Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds
Bioorg Med Chem. 2024 Apr 23;105:117734. doi: 10.1016/j.bmc.2024.117734. Online ahead of print.ABSTRACTAlthough cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of ...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Kristina Pavi ć Goran Poje Lais Pessanha de Carvalho Tana Tandari ć Marina Marinovi ć Diana Fontinha Jana Held Miguel Prud êncio Ivo Piantanida Robert Vianello Ivona Kro šl Knežević Ivana Perkovi ć Zrinka Raji ć Source Type: research
Optimization of benzenesulfonyl derivatives as anti-Trypanosomatidae agents: Structural design, synthesis, and pharmacological assessment against Trypanosoma cruzi and Leishmania infantum
This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in t...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Guilherme Freitas de Lima Hercos Mariza Gabriela Faleiro de Moura Lodi Cruz Ana Clara Cassiano Martinho Daniela de Melo Resende Danilo Farago Nascimento Paula Derksen Macruz Eduardo Jorge Pilau Silvane Maria Fonseca Murta Celso de Oliveira Rezende J únio Source Type: research
Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds
Bioorg Med Chem. 2024 Apr 23;105:117734. doi: 10.1016/j.bmc.2024.117734. Online ahead of print.ABSTRACTAlthough cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of ...
Source: Bioorganic and Medicinal Chemistry - April 27, 2024 Category: Chemistry Authors: Kristina Pavi ć Goran Poje Lais Pessanha de Carvalho Tana Tandari ć Marina Marinovi ć Diana Fontinha Jana Held Miguel Prud êncio Ivo Piantanida Robert Vianello Ivona Kro šl Knežević Ivana Perkovi ć Zrinka Raji ć Source Type: research
1,2,3-Triazole-totarol conjugates as potent PIP5K1 α lipid kinase inhibitors
Bioorg Med Chem. 2024 Apr 23;105:117727. doi: 10.1016/j.bmc.2024.117727. Online ahead of print.ABSTRACTThe human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02...
Source: Bioorganic and Medicinal Chemistry - April 26, 2024 Category: Chemistry Authors: Samer Haidar Ángel Amesty Sandra Oramas-Royo Claudia G ötz Ehab El-Awaad Jana Kaiser Sarah B ödecker Amelie Arnold Dagmar Aichele Juan M Amaro-Luis Ana Est évez-Braun Joachim Jose Source Type: research
1,2,3-Triazole-totarol conjugates as potent PIP5K1 α lipid kinase inhibitors
Bioorg Med Chem. 2024 Apr 23;105:117727. doi: 10.1016/j.bmc.2024.117727. Online ahead of print.ABSTRACTThe human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02...
Source: Bioorganic and Medicinal Chemistry - April 26, 2024 Category: Chemistry Authors: Samer Haidar Ángel Amesty Sandra Oramas-Royo Claudia G ötz Ehab El-Awaad Jana Kaiser Sarah B ödecker Amelie Arnold Dagmar Aichele Juan M Amaro-Luis Ana Est évez-Braun Joachim Jose Source Type: research
Molecular basis of N-glycan recognition by pradimicin a and its potential as a SARS-CoV-2 entry inhibitor
Bioorg Med Chem. 2024 Apr 18;105:117732. doi: 10.1016/j.bmc.2024.117732. Online ahead of print.ABSTRACTVirus entry inhibitors are emerging as an attractive class of therapeutics for the suppression of viral transmission. Naturally occurring pradimicin A (PRM-A) has received particular attention as the first-in-class entry inhibitor that targets N-glycans present on viral surface. Despite the uniqueness of its glycan-targeted antiviral activity, there is still limited knowledge regarding how PRM-A binds to viral N-glycans. Therefore, in this study, we performed binding analysis of PRM-A with synthetic oligosaccharides that ...
Source: Bioorganic and Medicinal Chemistry - April 21, 2024 Category: Chemistry Authors: Yu Nakagawa Masato Fujii Nanaka Ito Makoto Ojika Dai Akase Misako Aida Takaaki Kinoshita Yasuteru Sakurai Jiro Yasuda Yasuhiro Igarashi Yukishige Ito Source Type: research
Molecular basis of N-glycan recognition by pradimicin a and its potential as a SARS-CoV-2 entry inhibitor
Bioorg Med Chem. 2024 Apr 18;105:117732. doi: 10.1016/j.bmc.2024.117732. Online ahead of print.ABSTRACTVirus entry inhibitors are emerging as an attractive class of therapeutics for the suppression of viral transmission. Naturally occurring pradimicin A (PRM-A) has received particular attention as the first-in-class entry inhibitor that targets N-glycans present on viral surface. Despite the uniqueness of its glycan-targeted antiviral activity, there is still limited knowledge regarding how PRM-A binds to viral N-glycans. Therefore, in this study, we performed binding analysis of PRM-A with synthetic oligosaccharides that ...
Source: Bioorganic and Medicinal Chemistry - April 21, 2024 Category: Chemistry Authors: Yu Nakagawa Masato Fujii Nanaka Ito Makoto Ojika Dai Akase Misako Aida Takaaki Kinoshita Yasuteru Sakurai Jiro Yasuda Yasuhiro Igarashi Yukishige Ito Source Type: research
Molecular basis of N-glycan recognition by pradimicin a and its potential as a SARS-CoV-2 entry inhibitor
Bioorg Med Chem. 2024 Apr 18;105:117732. doi: 10.1016/j.bmc.2024.117732. Online ahead of print.ABSTRACTVirus entry inhibitors are emerging as an attractive class of therapeutics for the suppression of viral transmission. Naturally occurring pradimicin A (PRM-A) has received particular attention as the first-in-class entry inhibitor that targets N-glycans present on viral surface. Despite the uniqueness of its glycan-targeted antiviral activity, there is still limited knowledge regarding how PRM-A binds to viral N-glycans. Therefore, in this study, we performed binding analysis of PRM-A with synthetic oligosaccharides that ...
Source: Bioorganic and Medicinal Chemistry - April 21, 2024 Category: Chemistry Authors: Yu Nakagawa Masato Fujii Nanaka Ito Makoto Ojika Dai Akase Misako Aida Takaaki Kinoshita Yasuteru Sakurai Jiro Yasuda Yasuhiro Igarashi Yukishige Ito Source Type: research
M < sub > 1 < /sub > /M < sub > 4 < /sub > receptors as potential therapeutic treatments for schizophrenia: A comprehensive study
Bioorg Med Chem. 2024 Apr 16;105:117728. doi: 10.1016/j.bmc.2024.117728. Online ahead of print.ABSTRACTMuscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtyp...
Source: Bioorganic and Medicinal Chemistry - April 19, 2024 Category: Chemistry Authors: Lingsheng Fu Yi Luo Longyan Niu Ying Lin Xingru Chen Junhao Zhang Weifang Tang Yadong Chen Yu Jiao Source Type: research
Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas
In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 m...
Source: Bioorganic and Medicinal Chemistry - April 19, 2024 Category: Chemistry Authors: Di Wu Xiaoyi Zeng Yuanhao Zhao Mingze Qin Ping Gong Source Type: research
