Antitumor studies on celastrol and its derivatives as ROR α agonists and RORγ inhibitors based on Alphafold reverse docking strategy
AbstractCelastrol (CSL), an active compound extracted from the root bark ofTripterygium wilfordii, has been studied for its outstanding efficacy in anti-cancer and cerebral neurology. We have obtained a series of derivatives with reduced toxicity through biotransformation. Here, 23391 proteins of homo sapiens from AlphaFold DB and Schr ödinger’s Glide were used for reverse docking with the basic scaffold of CSL to discover the pharmacological activity of its derivatives. Based on the drug target database, the targets selected for the study were the RORα and RORγ of the Retinoic Acid Related-Orphan Receptors family (RO...
Source: Medicinal Chemistry Research - April 12, 2024 Category: Chemistry Source Type: research
Phenoxyalkyl cyclic and acyclic amine derivatives: what do they teach us about scaffold-based drug design?
AbstractFragment-based drug design of new bioactive scaffolds is a recent aspect of medicinal chemistry that provides a faster and more efficient road in drug discovery. Phenoxyethyl piperidine and morpholine derivatives have various pharmacological activities, from antitussive to anticancer properties. They are also widely used in selective estrogen receptor modulator (SERM) drugs and can be used to prevent osteoporosis in postmenopausal women. Also, other recent findings suggest that these compounds exhibit high anticholinergic and H3 inverse agonistic activities. We outlined the process of developing novel medications f...
Source: Medicinal Chemistry Research - April 10, 2024 Category: Chemistry Source Type: research
Synthesis and anticancer activity of novel coumarin-stilbene hybrids with different hydrocarbon chains as linkers
AbstractStilbene derivatives (pterostilbene and resveratrol) and 4-methylumbelliferone occur naturally in plants. These compounds and coumarin-stilbene hybrids have a variety of biological activities. It was envisioned that the molecular hybridization strategy would produce new bioactive molecules. Thus, six new coumarin-stilbene hybrids (3a-b, 4a-b, and 5a-b) with different hydrocarbon chains as linkers were synthesized by theO-alkylation reaction and characterized using FTIR,1H NMR,13C NMR, DEPT-135, and HRMS (ESI+) spectral analysis. An MTT assay was used to test the synthesized hybrids against breast cancer (MCF-7 andT...
Source: Medicinal Chemistry Research - April 5, 2024 Category: Chemistry Source Type: research
Vital residues-orientated rational design of butenolide inhibitors targeting Of ChtI
In this study, we employed a rational approach to design and synthesize a library of butenolide analogues (Ia-f andIIa-f) targeting Trp107, utilizing reported piperonyl butenolide as lead compound. Notably, the most compoundsIIa-f (R2 = NO2) exhibited slightly higher inhibitory potency againstOf ChtI compared to compoundsIa-f (R2 = Br). Molecular mechanism studies unveiled a crucial hydrogen bond interaction between the NO2 group and Trp107, explaining the enhanced binding affinities. CompoundsIIe andIIf, both bearing NO2 on the benzene ring at the R2 position, displayed the highest inhibitory activity, withKi valu...
Source: Medicinal Chemistry Research - April 2, 2024 Category: Chemistry Source Type: research
Design, synthesis and antitumor activity evaluation of novel benzamide HDAC inhibitors
AbstractIn recent years, histone deacetylase (HDAC) has become one of the hottest and most effective targets for the treatment of cancer. In this work, we designed and synthesized a series of novelo-aminobenzamide based HDAC inhibitors and evaluated their antitumor properties in vitro. All 23 compounds obtained showed micromolar IC50 values against A549 cells proliferation, and the most effective compound was8 u (IC50 = 0.165 μM). In vitro,8 u showed potent antiproliferative activity against another three cancer cell lines, outperforming the approved drug Chidamide. Enzyme inhibition and western blot assays confir...
Source: Medicinal Chemistry Research - March 28, 2024 Category: Chemistry Source Type: research
Design, synthesis, and in vitro biological evaluation of novel HDAC inhibitors bearing C-1 phenyl substituted tetrahydroisoquinoline Cap moiety as anti-tumor therapeutic agents
AbstractHerein, a structurally novel class of histone deacetylase (HDAC) inhibitors featuring the C-1 phenyl substituted tetrahydroisoquinoline Cap moiety were designed, synthesized, biologically evaluated in vitro and structure-activity relationship (SAR) study. A majority of compounds exhibited potent inhibitory activity against both HDAC6 and HDAC1 with IC50 in the two-digit nanomolar. The representative compound in this series,9g, demonstrated IC50 values of 1.89 ± 0.08, 0.63 ± 0.05, and 2.31 ± 0.06 μM against A549, RPMI 8226 and HepG2 cell line, respectively. The apoptosis assay demonstrated that9g ...
Source: Medicinal Chemistry Research - March 27, 2024 Category: Chemistry Source Type: research
Diffractaic acid and its ethers as anti-respiratory syncytial virus agents
AbstractA major secondary metabolite of lichens, diffractaic acid, was found here to exert a significant antiviral action on respiratory syncytial virus strain A2 with a EC50 of 4.8 µM while showing low toxicity to a tested cell line (CC50 of 221.9 µM). We developed methods for the synthesis of derivatives at the hydroxyl group of diffractaic acid and obtained three series of new derivatives: those of diffractaic acid and of its methyl and benzyl esters. We noted that the most promising compounds are derivatives of benzyldiffractate, which typically were found to have same or lower cytotoxicity as compared to eithe...
Source: Medicinal Chemistry Research - March 11, 2024 Category: Chemistry Source Type: research
Motor and non-motor symptoms, drugs, and their mode of action in Parkinson ’s disease (PD): a review
AbstractParkinson ’s disease is second most common neurodegenerative disorder neurological illness that primarily affects patients in their later years of life. Specific neurons in the brain begin to malfunction resulting in a loss of a substance called dopamine which is characterized by the accumulation of α-synu clein aggregates within cells, forming structures known as Lewy bodies and Lewy neurites. It is affecting more than 1% of people worldwide (aged 65 and above) and is expected to increase in prevalence by 2030. Muscle rigidity, tremor, and unresponsiveness of motion are some of the motor signs of thi s conditio...
Source: Medicinal Chemistry Research - March 7, 2024 Category: Chemistry Source Type: research
Synthesis, urease inhibitory and anticancer evaluation of glucosamine-sulfonylurea conjugates
AbstractUrease catalyses the hydrolysis of urea to ammonia and carbon dioxide. This enzyme is important in the virulence of several human pathogens and urease activity in soil can cleave urea fertilisers prematurely, leading to waste of agricultural nitrogen. A series of arylsulfonylurea-glucosamine hybrid compounds were synthesised. Reaction of arylsulfonamides with phenyl chloroformate and 4-dimethylaminopyridine gave either phenyl N-(2,4-arylsulfonyl)carbamate 4-dimethylaminopyridinium salts or N-(4-arylsulfonyl)-4-dimethylaminopyridinium-1-carboxamide inner salts, depending on the substitution on the arylsulfonamide. B...
Source: Medicinal Chemistry Research - March 7, 2024 Category: Chemistry Source Type: research
Motor and non-motor symptoms, drugs, and their mode of action in Parkinson ’s disease (PD): a review
AbstractParkinson ’s disease is second most common neurodegenerative disorder neurological illness that primarily affects patients in their later years of life. Specific neurons in the brain begin to malfunction resulting in a loss of a substance called dopamine which is characterized by the accumulation of α-synu clein aggregates within cells, forming structures known as Lewy bodies and Lewy neurites. It is affecting more than 1% of people worldwide (aged 65 and above) and is expected to increase in prevalence by 2030. Muscle rigidity, tremor, and unresponsiveness of motion are some of the motor signs of thi s conditio...
Source: Medicinal Chemistry Research - March 7, 2024 Category: Chemistry Source Type: research
Synthesis, urease inhibitory and anticancer evaluation of glucosamine-sulfonylurea conjugates
AbstractUrease catalyses the hydrolysis of urea to ammonia and carbon dioxide. This enzyme is important in the virulence of several human pathogens and urease activity in soil can cleave urea fertilisers prematurely, leading to waste of agricultural nitrogen. A series of arylsulfonylurea-glucosamine hybrid compounds were synthesised. Reaction of arylsulfonamides with phenyl chloroformate and 4-dimethylaminopyridine gave either phenyl N-(2,4-arylsulfonyl)carbamate 4-dimethylaminopyridinium salts or N-(4-arylsulfonyl)-4-dimethylaminopyridinium-1-carboxamide inner salts, depending on the substitution on the arylsulfonamide. B...
Source: Medicinal Chemistry Research - March 7, 2024 Category: Chemistry Source Type: research
Evaluation of ortho-substituted Bis-Functionalized Triazoles as Tyrosinase Inhibitors: Modulating Dopamine Synthesis and Behavior in Zebrafish
AbstractFacile and green chemistry pathways are utilized through microwave-assisted organic synthesis (MAOS) to generate biologically activeortho-substituted bis-functionalized triazole derivatives (C1-C7) in one step. MAOS expedited the process by improving reaction times (from 24 hours to 15–20 minutes) and provided the triazoles with good to excellent yields. Zebrafish based physiological and morphological analyses were carried out and most synthesized triazole compounds showed a significantly increased heart rate and growth in Zebrafish. The maximum tolerable dose ( MTD) of these compounds were identified to be ...
Source: Medicinal Chemistry Research - March 6, 2024 Category: Chemistry Source Type: research
Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction
AbstractIsatin (indol-2,3-dione), a secondary metabolite of tryptophan, has been used as the core structure to design several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogs of isatin hybrids have been synthesized and characterized, and their activities were established as inhibitors of both Aurora A kinase and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike/host angiotensin-converting enzyme II (ACE2) interactions. Amongst the synthesized isatin hybrids, compounds6a,6f,6g, a...
Source: Medicinal Chemistry Research - March 5, 2024 Category: Chemistry Source Type: research
