Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis
In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 μM), 1e (IC50 4.8 μM), and 1i (IC50 5.2 μM) exhibited potencies equivalent to MTZ (IC50 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 μM) and 48 h (IC50 2.1 μM). Additionally, all compounds demonstrated either no...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Rafaela Corr êa Silva Anna De Freitas Bruno Vicente Victor Midlej Maur ício Silva Dos Santos Source Type: research
A chemical magnet: Approaches to guide precise protein localization
Bioorg Med Chem. 2024 Mar 2;102:117672. doi: 10.1016/j.bmc.2024.117672. Online ahead of print.ABSTRACTSmall molecules that chemically induce proximity between two proteins have been widely used to precisely modulate protein levels, stability, and activity. Recently, several studies developed novel strategies that employ heterobifunctional molecules that co-opt shuttling proteins to control the spatial localization of a target protein, unlocking new potential within this domain. Together, these studies lay the groundwork for novel targeted protein relocalization modalities that can rewire the protein circuitry and interacto...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Saurav Kumar Behnam Nabet Source Type: research
Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis
In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 μM), 1e (IC50 4.8 μM), and 1i (IC50 5.2 μM) exhibited potencies equivalent to MTZ (IC50 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 μM) and 48 h (IC50 2.1 μM). Additionally, all compounds demonstrated either no...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Rafaela Corr êa Silva Anna De Freitas Bruno Vicente Victor Midlej Maur ício Silva Dos Santos Source Type: research
A chemical magnet: Approaches to guide precise protein localization
Bioorg Med Chem. 2024 Mar 2;102:117672. doi: 10.1016/j.bmc.2024.117672. Online ahead of print.ABSTRACTSmall molecules that chemically induce proximity between two proteins have been widely used to precisely modulate protein levels, stability, and activity. Recently, several studies developed novel strategies that employ heterobifunctional molecules that co-opt shuttling proteins to control the spatial localization of a target protein, unlocking new potential within this domain. Together, these studies lay the groundwork for novel targeted protein relocalization modalities that can rewire the protein circuitry and interacto...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Saurav Kumar Behnam Nabet Source Type: research
Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis
In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 μM), 1e (IC50 4.8 μM), and 1i (IC50 5.2 μM) exhibited potencies equivalent to MTZ (IC50 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 μM) and 48 h (IC50 2.1 μM). Additionally, all compounds demonstrated either no...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Rafaela Corr êa Silva Anna De Freitas Bruno Vicente Victor Midlej Maur ício Silva Dos Santos Source Type: research
A chemical magnet: Approaches to guide precise protein localization
Bioorg Med Chem. 2024 Mar 2;102:117672. doi: 10.1016/j.bmc.2024.117672. Online ahead of print.ABSTRACTSmall molecules that chemically induce proximity between two proteins have been widely used to precisely modulate protein levels, stability, and activity. Recently, several studies developed novel strategies that employ heterobifunctional molecules that co-opt shuttling proteins to control the spatial localization of a target protein, unlocking new potential within this domain. Together, these studies lay the groundwork for novel targeted protein relocalization modalities that can rewire the protein circuitry and interacto...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Saurav Kumar Behnam Nabet Source Type: research
Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis
In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 μM), 1e (IC50 4.8 μM), and 1i (IC50 5.2 μM) exhibited potencies equivalent to MTZ (IC50 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 μM) and 48 h (IC50 2.1 μM). Additionally, all compounds demonstrated either no...
Source: Bioorganic and Medicinal Chemistry - March 10, 2024 Category: Chemistry Authors: Rafaela Corr êa Silva Anna De Freitas Bruno Vicente Victor Midlej Maur ício Silva Dos Santos Source Type: research
Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A
Bioorg Med Chem. 2024 Feb 27;102:117658. doi: 10.1016/j.bmc.2024.117658. Online ahead of print.ABSTRACTAurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) ...
Source: Bioorganic and Medicinal Chemistry - March 9, 2024 Category: Chemistry Authors: Hyomin Lee Euijung Kim Narae Hwang Jesik Yoo Yunju Nam Injeoung Hwang Jin-Gyeong Park Sang-Eun Park Kyung-Sook Chung Hwan Won Chung Chiman Song Mi-Jung Ji Hyun-Mee Park In-Kyun Lee Kyung-Tae Lee Eun Joo Roh Wooyoung Hur Source Type: research
Development of an oxazole-based cleavable linker for peptides
We report the development of a new oxazole-based cleavable linker to release peptides from attached cargo. Oxazoles are stable to most reaction conditions, yet they can be rapidly cleaved in the presence of single-electron oxidants like cerium ammonium nitrate (CAN). An oxazole linker could be synthesized and attached to peptides through standard solid-phase peptide coupling reactions. Cleavage of these peptide-oxazole conjugates is demonstrated on a broad scope of peptides containing various natural and unnatural amino acids. These results represent the first example of a peptide-based linker that is cleaved through singl...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Elizabeth L Taggart Evan J Wolff Pamira Yanar John P Blobe Christopher R Shugrue Source Type: research
Casitas b cell lymphoma ‑B (Cbl-b): A new therapeutic avenue for small-molecule immunotherapy
Bioorg Med Chem. 2024 Mar 6;102:117677. doi: 10.1016/j.bmc.2024.117677. Online ahead of print.ABSTRACTImmunotherapy has revolutionized the area of cancer treatment. Although most immunotherapies now are antibodies targeting membrane checkpoint molecules, there is an increasing demand for small-molecule drugs that address intracellular pathways. The E3 ubiquitin ligase Casitas B cell lymphoma‑b (Cbl-b) has been regarded as a promising intracellular immunotherapy target. Cbl-b regulates the downstream proteins of multiple membrane receptors and co-receptors, restricting the activation of the innate and adaptive immune syst...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Xiuqi Hu Erdong Li Yangguo Zhou Qidong You Zhengyu Jiang Source Type: research
Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers
Bioorg Med Chem. 2024 Mar 2;102:117674. doi: 10.1016/j.bmc.2024.117674. Online ahead of print.ABSTRACTControlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug-drug conjugates (DDCs)...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Hikaru Fujita Sachiko Arai Hiroshi Arakawa Kana Hamamoto Toshiyuki Kato Tsubasa Arai Nanaka Nitta Kazuki Hotta Natsuko Hosokawa Takako Ohbayashi Chiaki Takahashi Yasuhide Inokuma Ikumi Tamai Seiji Yano Munetaka Kunishima Yoshihiro Watanabe Source Type: research
Development of an oxazole-based cleavable linker for peptides
We report the development of a new oxazole-based cleavable linker to release peptides from attached cargo. Oxazoles are stable to most reaction conditions, yet they can be rapidly cleaved in the presence of single-electron oxidants like cerium ammonium nitrate (CAN). An oxazole linker could be synthesized and attached to peptides through standard solid-phase peptide coupling reactions. Cleavage of these peptide-oxazole conjugates is demonstrated on a broad scope of peptides containing various natural and unnatural amino acids. These results represent the first example of a peptide-based linker that is cleaved through singl...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Elizabeth L Taggart Evan J Wolff Pamira Yanar John P Blobe Christopher R Shugrue Source Type: research
Casitas b cell lymphoma ‑B (Cbl-b): A new therapeutic avenue for small-molecule immunotherapy
Bioorg Med Chem. 2024 Mar 6;102:117677. doi: 10.1016/j.bmc.2024.117677. Online ahead of print.ABSTRACTImmunotherapy has revolutionized the area of cancer treatment. Although most immunotherapies now are antibodies targeting membrane checkpoint molecules, there is an increasing demand for small-molecule drugs that address intracellular pathways. The E3 ubiquitin ligase Casitas B cell lymphoma‑b (Cbl-b) has been regarded as a promising intracellular immunotherapy target. Cbl-b regulates the downstream proteins of multiple membrane receptors and co-receptors, restricting the activation of the innate and adaptive immune syst...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Xiuqi Hu Erdong Li Yangguo Zhou Qidong You Zhengyu Jiang Source Type: research
Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers
Bioorg Med Chem. 2024 Mar 2;102:117674. doi: 10.1016/j.bmc.2024.117674. Online ahead of print.ABSTRACTControlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug-drug conjugates (DDCs)...
Source: Bioorganic and Medicinal Chemistry - March 8, 2024 Category: Chemistry Authors: Hikaru Fujita Sachiko Arai Hiroshi Arakawa Kana Hamamoto Toshiyuki Kato Tsubasa Arai Nanaka Nitta Kazuki Hotta Natsuko Hosokawa Takako Ohbayashi Chiaki Takahashi Yasuhide Inokuma Ikumi Tamai Seiji Yano Munetaka Kunishima Yoshihiro Watanabe Source Type: research
Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound
We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3') and PEG-type linkers were assessed, to obtain a linked-hit molecul...
Source: Bioorganic and Medicinal Chemistry - March 7, 2024 Category: Chemistry Authors: C Kieffer N Primas S Hutter A Merckx L Reininger S Bach S Ruchaud F Gaillard M Laget D Amrane L Herv é C Castera-Ducros J Renault A Dum ètre S Rault C Doerig P Rathelot P Vanelle N Azas P Verhaeghe Source Type: research
