journal
https://read.qxmd.com/read/37681210/development-of-convenient-crystallization-inhibition-assays-for-structure-activity-relationship-studies-in-the-discovery-of-crystallization-inhibitors
#1
JOURNAL ARTICLE
Jeffrey Yang, Haifa Albanyan, Yiling Wang, Yanhui Yang, Amrik Sahota, Longqin Hu
Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies...
July 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37362321/successes-in-antiviral-drug-discovery-a-tribute-to-nick-meanwell
#2
REVIEW
David P Rotella
Drug discovery is a difficult task, and is even more challenging when the target evolves during therapy. Antiviral drug therapy is an excellent example, exemplified by the evolution of therapeutic approaches for treatment of hepatitis C and HIV-1. Nick Meanwell and his colleagues made important contributions leading to molecules for treatment of hepatitis C and HIV-1, each with distinct mechanisms of action. This review summarizes the discovery and impact of these drugs, and will highlight, where applicable, the broader contributions of these discoveries to medicinal chemistry and drug discovery...
June 8, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37362320/discovery-of-pyrrolo-2-1-f-1-2-4-triazine-based-inhibitors-of-adaptor-protein-2-associated-kinase-1-for-the-treatment-of-pain
#3
Carolyn D Dzierba, Bireshwar Dasgupta, George Karageorge, Walter Kostich, Brian Hamman, Jason Allen, Kim M Esposito, Ramesh Padmanabha, James Grace, Kimberley Lentz, John Morrison, Daniel Morgan, Amy Easton, Clotilde Bourin, Marc R Browning, Ramkumar Rajamani, Andrew Good, Dawn D Parker, Jodi K Muckelbauer, Javed Khan, Daniel Camac, Kaushik Ghosh, Vivek Halan, Jonathan S Lippy, Kenneth S Santone, R Rex Denton, Ryan Westphal, Linda J Bristow, Charles M Conway, Joanne J Bronson, John E Macor
Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1- f ][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1...
June 3, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37362318/amide-and-bis-amide-linked-highly-potent-and-broadly-active-antifungal-agents-for-the-treatment-of-invasive-fungal-infections-towards-the-discovery-of-pre-clinical-development-candidate-fc12406
#4
JOURNAL ARTICLE
Simon D P Baugh, Anna Chaly, Damian G Weaver, David B Whitman, Jeffrey C Pelletier, Haiyan Bian, Katie B Freeman, Allen B Reitz, Richard W Scott
Most fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives...
May 30, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37362317/recent-insights-into-antibacterial-potential-of-benzothiazole-derivatives
#5
REVIEW
Priyanka Kashyap, Sangeeta Verma, Pankaj Gupta, Rakesh Narang, Sukhbir Lal, Manish Devgun
Antimicrobial resistance (AMR) is a worldwide concern among infectious diseases due to increased mortality, morbidity and treatment cost. According to WHO 2019 report, among the 32 antibiotics in the clinical trials, only six were classified as innovative and containing novel moiety. The remaining antibiotics from this list contain previously known moiety (WHO AMR 2019). Therefore, the development of novel antibiotics to control resistance problems is crucial. Benzothiazole derivatives are of great interest due to their wide range of biological activities and medicinal applications...
May 29, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37362319/the-pyridazine-heterocycle-in-molecular-recognition-and-drug-discovery
#6
REVIEW
Nicholas A Meanwell
The pyridazine ring is endowed with unique physicochemical properties, characterized by weak basicity, a high dipole moment that subtends π-π stacking interactions and robust, dual hydrogen-bonding capacity that can be of importance in drug-target interactions. These properties contribute to unique applications in molecular recognition while the inherent polarity, low cytochrome P450 inhibitory effects and potential to reduce interaction of a molecule with the cardiac hERG potassium channel add additional value in drug discovery and development...
March 15, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/36816432/design-synthesis-and-anti-breast-cancer-properties-of-butyric-ester-tethered-dihydroartemisinin-isatin-hybrids
#7
JOURNAL ARTICLE
Shijia Zhao, Xiaoyan Zhang, Min Tang, Xiaocheng Liu, Jialun Deng, Wei Zhou, Zhi Xu
Fifteen novel butyric ester tethered dihydroartemisinin-isatin hybrids 4a-d and 5a-k were designed, synthesized, and evaluated for cytotoxicity against four human breast cancer cell lines, including MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR using the MTT method. A significant part of them were active against the four tested cancer cell lines, and the representative hybrid 5b (IC50 : 1.27 µM) was 14.88 -> 78.74 times more active than adriamycin (IC50 : 18.90 µM), DHA (IC50 : 28...
February 14, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/36713891/novel-benzo-4-5-imidazo-1-2-a-pyrimidine-derivatives-as-selective-cyclooxygenase-2-inhibitors-design-synthesis-docking-studies-and-biological-evaluation
#8
JOURNAL ARTICLE
Maryam Bayanati, Mona Khoramjouy, Mehrdad Faizi, Mahsa Azami Movahed, Mohammad Mahboubi-Rabbani, Afshin Zarghi
The present study was aimed at the synthesis and evaluation of a new series of benzo[4,5]imidazo[1,2- a ]pyrimidine having a methylsulfonyl group as COX-2 (cyclooxygenase-2) inhibitor pharmacophore. Molecular modeling studies were performed using the Autodock program, and the results demonstrated that methylsulfonyl pharmacophore was adequately placed into the COX-2 active site. The in vitro and in vivo COX-2 inhibitory effects were also evaluated. In the in vitro assay, all newly synthesized compounds showed moderate to good selectivity for the inhibition of the COX-2 enzyme...
January 23, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/36694836/mannose-a-potential-saccharide-candidate-in-disease-management
#9
REVIEW
M Dhanalakshmi, D Sruthi, K R Jinuraj, Kajari Das, Sushma Dave, N Muthulakshmi Andal, Jayashankar Das
There are a plethora of antibiotic resistance cases and humans are marching towards another big survival test of evolution along with drastic climate change and infectious diseases. Ever since the first antibiotic [penicillin], and the myriad of vaccines, we were privileged to escape many infectious disease threats. The survival technique of pathogens seems rapidly changing and sometimes mimicking our own systems in such a perfect manner that we are left unarmed against them. Apart from searching for natural alternatives, repurposing existing drugs more effectively is becoming a familiar approach to new therapeutic opportunities...
January 20, 2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37305209/an-update-on-the-discovery-and-development-of-reversible-covalent-inhibitors
#10
REVIEW
Faridoon, Raymond Ng, Guiping Zhang, Jie Jack Li
Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37305208/promising-schiff-bases-in-antiviral-drug-design-and-discovery
#11
REVIEW
Shikha Kaushik, Sarvesh Kumar Paliwal, Malliga R Iyer, Vaishali M Patil
Emerging and re-emerging illnesses will probably present a new hazard of infectious diseases and have fostered the urge to research new antiviral agents. Most of the antiviral agents are analogs of nucleosides and only a few are non-nucleoside antiviral agents. There is quite a less percentage of marketed/clinically approved non-nucleoside antiviral medications. Schiff bases are organic compounds that possess a well-demonstrated profile against cancer, viruses, fungus, and bacteria, as well as in the management of diabetes, chemotherapy-resistant cases, and malarial infections...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37305207/design-synthesis-biochemical-and-in-silico-characterization-of-novel-naphthalene-thiourea-conjugates-as-potential-and-selective-inhibitors-of-alkaline-phosphatase
#12
JOURNAL ARTICLE
Aamer Saeed, Saba Ashraf, Mubashir Aziz, Pervaiz Ali Channar, Syeda Abida Ejaz, Ammara Fayyaz, Qamar Abbas, Fatmah Ali Alasmary, Abdulnasser Mahmoud Karami, Arfa Tehzeeb, Amara Mumtaz, Hesham R El-Seedi
Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates ( 5a-5j ) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37305206/design-synthesis-molecular-docking-study-and-molecular-dynamics-simulation-of-new-coumarin-pyrimidine-hybrid-compounds-having-anticancer-and-antidiabetic-activity
#13
JOURNAL ARTICLE
Duong Ngoc Toan, Nguyen Dinh Thanh, Mai Xuan Truong, Dinh Thuy Van, Nguyen Ngoc Thanh
Coumarin-pyrimidine hybrid compounds were synthesized by condensation reaction of α,β-unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin with guanidine. The reaction yields were of 42-62%. The antidiabetic and anticancer activities of these compounds were examined. These compounds displayed low toxicity to two cancer cell lines (including KB and HepG2 ones), but exhibited remarkably active against α-amylase with IC50 values of 102.32 ± 1.15 μM to 249...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37056462/synthesis-and-biological-evaluation-of-esculetin-derivatives-as-potential-anti-hbv-agents
#14
JOURNAL ARTICLE
Zhen Ye, Tong-Shi-Yao Zhao, Shan-Bin Li, Xian-Li Zhou, Qin Luo, Jiang-Ke Qin, Cheng-Qin Liang, Ping Wang, Guang-Bo Ge
Previous in vivo and in vitro studies revealed that esculetin (Fig. 1) has anti-hepatitis B virus (anti-HBV) activity as well as a protective effect on liver damage caused by duck hepatitis B virus. We designed and synthesized a series of esculetin derivatives, introduced side chains containing various amino groups into site 7 of the parent structure, and synthesized C-4 and C-8 substituted derivatives with the goal of investigating their anti-HBV activities. In vitro anti-HBV activity was performed against HepG2...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/37056461/design-synthesis-and-biological-evaluation-of-new-2-4-methylsulfonyl-phenyl-n-phenylimidazo-1-2-a-pyridin-3-amine-as-selective-cox-2-inhibitors
#15
JOURNAL ARTICLE
Mahsa Azami Movahed, Fatemeh Khadem Abbasi, Mahsa Rajabi, Niusha Abedi, Nima Naderi, Bahram Daraei, Afshin Zarghi
Cyclooxygenase (COX), which plays a role in converting arachidonic acid to inflammatory mediators, could be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Although potent NSAIDs are available for the treatment of pain, fever, and inflammation, some side effects, such as gastrointestinal ulcers, limit the use of these medications. In recent years, selective COX-2 inhibitors with a lower incidence of adverse effects attained an important position in medicinal chemistry. In order to introduce some new potent COX-2 inhibitors, a new series of 2-(4-(methylsulfonyl)phenyl)- N -phenylimidazo[1,2- a ]pyridin-3-amines was designed, synthesized, and evaluated...
2023: Medicinal Chemistry Research
https://read.qxmd.com/read/36593869/evaluation-of-a-series-of-nucleoside-analogs-as-effective-anticoronaviral-2-drugs-against-the-omicron-b-1-1-529-ba-2-subvariant-a-repurposing-research-study
#16
JOURNAL ARTICLE
Amgad M Rabie, Mohnad Abdalla
Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic...
December 29, 2022: Medicinal Chemistry Research
https://read.qxmd.com/read/36593868/synthesis-and-bioactivity-evaluation-of-pachymic-acid-derivatives-as-potential-cytotoxic-agents
#17
JOURNAL ARTICLE
Hezhen Wang, Xun Sun, Chunyong Wei, Jing Wang, Yingshu Xu, Guohui Bai, Qizheng Yao, Lei Zhang
Pachymic acid, a well-known natural lanostane-type triterpenoid, exhibits various pharmacological properties. In this study, 18 derivatives of pachymic acid were synthesized by modifying their molecular structures and evaluated for their anticancer activity against two human cancer cell lines using the CCK-8 assay. Structure-activity relationship studies according to the in vitro cytotoxicity unexpectedly found one promising derivative A17 (namely tumulosic acid, also found in Poria cocos ), which had stronger anti-proliferative activity than the positive drug cisplatin against HepG2 and HSC-2 cell lines with IC50 values of 7...
December 29, 2022: Medicinal Chemistry Research
https://read.qxmd.com/read/37077288/novel-mreb-inhibitors-with-antibacterial-activity-against-gram-bacteria
#18
JOURNAL ARTICLE
Hye Yeon Sagong, Jesus D Rosado-Lugo, Eric J Bryan, Edgar Ferrer-González, Yiling Wang, Yanlu Cao, Ajit K Parhi, Daniel S Pilch, Edmond J LaVoie
MreB is a cytoskeleton protein present in rod-shaped bacteria that is both essential for bacterial cell division and highly conserved. Because most Gram (-) bacteria require MreB for cell division, chromosome segregation, cell wall morphogenesis, and cell polarity, it is an attractive target for antibacterial drug discovery. As MreB modulation is not associated with the activity of antibiotics in clinical use, acquired resistance to MreB inhibitors is also unlikely. Compounds, such as A22 and CBR-4830, are known to disrupt MreB function by inhibition of ATPase activity...
October 2022: Medicinal Chemistry Research
https://read.qxmd.com/read/37065467/combination-with-a-ftsz-inhibitor-potentiates-the-in-vivo-efficacy-of-oxacillin-against-methicillin-resistant-staphylococcus-aureus
#19
JOURNAL ARTICLE
Malvika Kaul, Edgar Ferrer-González, Lilly Mark, Ajit K Parhi, Edmond J LaVoie, Daniel S Pilch
Oxacillin is a first-line antibiotic for the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) infections but is ineffective against methicillin-resistant S. aureus (MRSA) due to resistance. Here we present results showing that co-administering oxacillin with the FtsZ-targeting prodrug TXA709 renders oxacillin efficacious against MRSA. The combination of oxacillin and the active product of TXA709 (TXA707) is associated with synergistic bactericidal activity against clinical isolates of MRSA that are resistant to current standard-of-care antibiotics...
October 2022: Medicinal Chemistry Research
https://read.qxmd.com/read/36193545/rna-dependent-rna-polymerase-rdrp-natural-antiviral-inhibitors-a-review
#20
REVIEW
Daniela Regina Buch Leite, Karen Mary Mantovani, Solange Pereira Cordeiro, Filipe Barros Maia, Fernando Cesar Martins Betim, Elisiane de Bona Sartor, Deise Prehs Montrucchio, Josiane de Fátima Gaspari Dias, Obdulio Gomes Miguel, Marilis Dallarmi Miguel
Viral diseases are the cause of many global epidemics, leading to deaths, affecting the quality of life of populations, and impairing public health. The limitations in the treatment of viral diseases and the constant resistance to conventional antiviral treatments encourage researchers to discover new compounds. In this perspective, this literature review presents isolated molecules and extracts of natural products capable of inhibiting the activity of the nonstructural protein that acts as the RNA-dependent RNA polymerase...
September 29, 2022: Medicinal Chemistry Research
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