Structure-guided design of novel biphenyl-quinazoline derivatives as potent non-nucleoside reverse transcriptase inhibitors featuring improved anti-resistance, selectivity, and solubility
Bioorg Chem. 2024 Apr 5;147:107340. doi: 10.1016/j.bioorg.2024.107340. Online ahead of print.ABSTRACTIn pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound ...
Source: Bioorganic Chemistry - April 9, 2024 Category: Chemistry Authors: Jin-Si Wang Ke-Xin Zhao Kun Zhang Christophe Pannecouque Erik De Clercq Shuai Wang Fen-Er Chen Source Type: research
Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential
In this study, uncleavable sequences were used to stage Ras isoforms in a farnesylated and uncleaved state to address the impact of CaaX proteolysis on protein localization and function. This targeted strategy is more specific than those that chemically inhibit the Rce1 CaaX protease or delete the RCE1 gene because global abrogation of CaaX proteolysis impacts the entire CaaX protein proteome and effects cannot be attributed to any specific CaaX protein of the many concurrently affected. With this targeted strategy, clear mislocalization and reduced activity of farnesylated and uncleaved Ras isoforms was observed. In addit...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Emily R Hildebrandt Shaneela A Hussain Michelle A Sieburg Rajani Ravishankar Nadeem Asad Sangram Gore Takahiro Ito James L Hougland Timothy M Dore Walter K Schmidt Source Type: research
Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy
This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.PMID:38583247 | DOI:10.1016/j.bioorg.2024.107325 (Source: Bioorganic Chemistry)
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Xi Sheng Meng-Meng Wang Guan-Dong Zhang Yan Su Hong-Bao Fang Zheng-Hong Yu Zhi Su Source Type: research
Novel partially reversible NDM-1 inhibitors based on the naturally occurring houttuynin
In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC50 range of 1.1-1.5 μM, while the shorter chain the weaker inhibition. Further synergistic experiments in c...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Lifang Wang Yaowen Liang Pan Luo Manna Huang Yiqian Wan Source Type: research
Design and synthesis of novel imidazole-chalcone derivatives as microtubule protein polymerization inhibitors to treat cervical cancer and reverse cisplatin resistance
Bioorg Chem. 2024 Apr 4;147:107310. doi: 10.1016/j.bioorg.2024.107310. Online ahead of print.ABSTRACTUsing the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activi...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Zhengye Liu Zheng Yang Mourboul Ablise Source Type: research
Natural anti-neuroinflammatory inhibitors in vitro and in vivo from Aglaia odorata
Bioorg Chem. 2024 Apr 4;147:107335. doi: 10.1016/j.bioorg.2024.107335. Online ahead of print.ABSTRACTFifty compounds including seven undescribed (1, 13, 18-20, 30, 31) and forty-three known (2-12, 14-17, 21-29, 32-50) ones were isolated from the extract of the twigs and leaves of Aglaia odorata with anti-neuroinflammatory activities. Their structures were determined by a combination of spectral analysis and calculated spectra (ECD and NMR). Among them, compounds 13-25 were found to possess tertiary amide bonds, with compounds 16, 17, and 19-21 existing detectable cis/trans mixtures in 1H NMR spectrum measured in CDCl3. Spe...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Qianqian Yin Gang Chen Danyang Mu Yuxin Yang Jinle Hao Bin Lin Di Zhou Yue Hou Ning Li Source Type: research
Dimeric peptoids as antibacterial agents
Bioorg Chem. 2024 Apr 3;147:107334. doi: 10.1016/j.bioorg.2024.107334. Online ahead of print.ABSTRACTBuilding upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal inter...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Ghayah Bahatheg Rajesh Kuppusamy Muhammad Yasir Samara Bridge Shyam K Mishra Charles G Cranfield David StC Black Mark Willcox Naresh Kumar Source Type: research
Discovery and development of novel 10,12-disubstituted aloperine derivatives against HCoV-OC43 by targeting allosteric site of host TMPRSS2
Bioorg Chem. 2024 Mar 27;147:107317. doi: 10.1016/j.bioorg.2024.107317. Online ahead of print.ABSTRACTBy inducing steric activation of the 10CH bond with a 12-acyl group to form a key imine oxime intermediate, 20 novel (10S)-10,12-disubstituted aloperine derivatives were successfully synthesized and assessed for their antiviral efficacy against HCoV-OC43. Of them, compound 3i exhibited the moderate activities against HCoV-OC43, as well as against the SARS-CoV-2 variant EG.5.1 with the comparable EC50 values of 4.7 and 4.1 μM. A mechanism study revealed that it inhibited the protease activity of host TMPRSS2 by binding to ...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Runze Meng Xiuli Zhong Yue Gong Yulong Shi Jiayu Li Zhiyun Wu Qionglu Duan Xintong Zhang Yuheng Mei Jingyang Zhu Zonggen Peng Yinghong Li Danqing Song Source Type: research
Antimicrobial macrozones interact with biological macromolecules via two-site binding mode of action: Fluorimetric, NMR and docking studies
Bioorg Chem. 2024 Apr 5;147:107338. doi: 10.1016/j.bioorg.2024.107338. Online ahead of print.ABSTRACTMacrozones are novel conjugates of azithromycin and thiosemicarbazones, which exhibit very good in vitro antibacterial activities against susceptible and some resistant bacterial strains thus showing a potential for further development. A combination of spectrometric (fluorimetry, STD and WaterLOGSY NMR) and molecular docking studies provided insights into atomic details of interactions between selected macrozones and biological receptors such as E. coli ribosome and bovine serum albumin. Fluorimetric measurements revealed ...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Tomislav Jedna čak Ivana Mikulandra Kristina Smokrovi ć Andrea Hlou šek-Kasun Monika Kapusti ć Kristina Dela š Ivo Piantanida Marta Jurkovi ć Branimir Berto ša Klaus Zangger Predrag Novak Source Type: research
PI3K δ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues
Bioorg Chem. 2024 Mar 30;147:107323. doi: 10.1016/j.bioorg.2024.107323. Online ahead of print.ABSTRACTPhosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Digambar Yevale Nishith Teraiya Twinkle Lalwani Mayur Dalasaniya Khushal Kapadiya Rakesh Kumar Ameta Chetan B Sangani Yong-Tao Duan Source Type: research
Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential
In this study, uncleavable sequences were used to stage Ras isoforms in a farnesylated and uncleaved state to address the impact of CaaX proteolysis on protein localization and function. This targeted strategy is more specific than those that chemically inhibit the Rce1 CaaX protease or delete the RCE1 gene because global abrogation of CaaX proteolysis impacts the entire CaaX protein proteome and effects cannot be attributed to any specific CaaX protein of the many concurrently affected. With this targeted strategy, clear mislocalization and reduced activity of farnesylated and uncleaved Ras isoforms was observed. In addit...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Emily R Hildebrandt Shaneela A Hussain Michelle A Sieburg Rajani Ravishankar Nadeem Asad Sangram Gore Takahiro Ito James L Hougland Timothy M Dore Walter K Schmidt Source Type: research
Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy
This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.PMID:38583247 | DOI:10.1016/j.bioorg.2024.107325 (Source: Bioorganic Chemistry)
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Xi Sheng Meng-Meng Wang Guan-Dong Zhang Yan Su Hong-Bao Fang Zheng-Hong Yu Zhi Su Source Type: research
Novel partially reversible NDM-1 inhibitors based on the naturally occurring houttuynin
In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC50 range of 1.1-1.5 μM, while the shorter chain the weaker inhibition. Further synergistic experiments in c...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Lifang Wang Yaowen Liang Pan Luo Manna Huang Yiqian Wan Source Type: research
Design and synthesis of novel imidazole-chalcone derivatives as microtubule protein polymerization inhibitors to treat cervical cancer and reverse cisplatin resistance
Bioorg Chem. 2024 Apr 4;147:107310. doi: 10.1016/j.bioorg.2024.107310. Online ahead of print.ABSTRACTUsing the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activi...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Zhengye Liu Zheng Yang Mourboul Ablise Source Type: research
Natural anti-neuroinflammatory inhibitors in vitro and in vivo from Aglaia odorata
Bioorg Chem. 2024 Apr 4;147:107335. doi: 10.1016/j.bioorg.2024.107335. Online ahead of print.ABSTRACTFifty compounds including seven undescribed (1, 13, 18-20, 30, 31) and forty-three known (2-12, 14-17, 21-29, 32-50) ones were isolated from the extract of the twigs and leaves of Aglaia odorata with anti-neuroinflammatory activities. Their structures were determined by a combination of spectral analysis and calculated spectra (ECD and NMR). Among them, compounds 13-25 were found to possess tertiary amide bonds, with compounds 16, 17, and 19-21 existing detectable cis/trans mixtures in 1H NMR spectrum measured in CDCl3. Spe...
Source: Bioorganic Chemistry - April 7, 2024 Category: Chemistry Authors: Qianqian Yin Gang Chen Danyang Mu Yuxin Yang Jinle Hao Bin Lin Di Zhou Yue Hou Ning Li Source Type: research
