Medicinal Chemistry Research最新文献

Although benzbromarone is a highly potent inhibitor of URAT1, the toxicity of its metabolite has led to the restricted use. In this study, to decrease its toxicity, thirteen benzbromarone derivatives were designed and synthesized via blocking metabolic site. Among them, most of the compounds had moderate to strong inhibitory activity against URAT1, with IC₅₀ values ranging from 0.041 ± 0.010 μM to 3.208 ± 0.458 μM. In particular, compound 30 demonstrated the most potent URAT1-inhibitory activity (IC₅₀ = 0.041 ± 0.010 μM), which is nearly seven-fold enhanced over BBR (IC₅₀ = 0.278 ± 0.053 μM). Importantly, it displayed a favorable bioavailability of 75.2%. As demonstrated by the in vitro and in vivo experiments, no reported toxic metabolites were found and the risk of potential liver toxicity was low.

In this study, a series of imidazo[2,1-b][1,3,4]thiadiazole derivatives were designed, synthesized, and evaluated as potential cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Furthermore, the antioxidant activities of these compounds were examined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The inhibition assay against cholinesterase (ChE) revealed that these synthesized compounds exhibited moderate inhibitory activities against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Notably, some of the tested compounds had varying antioxidant activities. Specifically, compound 20aa (eeAChE, IC₅₀ = 0.75 μM; eqBChE, IC₅₀ = 4.11 μM; SI = 5.48) was found to be the most effective ChEI, exhibiting approximately 5-fold greater activity against AChE and 4-fold greater activity against BChE compared to galantamine. Additionally, compound 20aa also possessed antioxidant activity, with IC₅₀ value of 442.87 µM. To understand the binding mode of compound 20aa, molecular docking studies were performed, and the results indicated that compound 20aa could interact with amino acid residues in the catalytic active site (CAS) of both BChE and AChE, as well as with the peripheral anionic site (PAS) of AChE. Among them, compound 20aa showed a mixed inhibition pattern with AChE, which aligned with the results of the enzyme kinetics studies. Molecular dynamics (MD) simulation studies demonstrated the stability of the 20aa-AChE/BChE complexes. Considering its biological activity and molecular properties, compound 20aa could be a promising lead compound for the development of AD drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained significant public health attention owing to its devastating effects on lives and livelihoods worldwide. Due to difficult access to vaccines in many developing countries and the inefficiency of vaccines in providing complete protection even with fully vaccinated persons, there remains the need for the development of novel drugs to combat the disease. This study describes the in vitro activity of a library of fifty-five spiro-fused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) as potential blocking agents of the interaction between the SARS-CoV-2 viral spike and the human angiotensin-converting enzyme 2 (ACE2) receptor, essential for viral transmission. The synthesis was conducted by the Pictet-Spengler condensation of phenethylamine and isatin derivatives, while the screening against spike-ACE2 interaction was done using our previously described AlphaScreen fluorescent assay. The in vitro screening identified compound (11j) as the most active, showing a 50% inhibitory concentration (IC₅₀) of 3.6 μM against SARS-CoV-2 spike/ACE2 interaction. Structure-activity relationships explained via molecular docking studies and the computation of binding free energy of each compound with respect to the spike/ACE2 protein-protein interaction showed that the most active compound possesses a bulky naphthyl group, which addresses voluminous hydrophobic regions of the ACE2 binding site and interacts with the hydrophobic residues of the target. Therefore, these compounds could be potentially useful in searching for SARS-CoV-2 spike/ACE2 interaction blocking agents.

Synthesis of hybrid molecules via molecular hybridization technique has been known to be a promising strategy which involves the blending of two pharmacophoric groups joined via covalent bonds to make a single entity that can serve as chemotherapeutic agents. “Isatin” is an important toolbox for medicinal chemists with high pharmacological profile being known as the “privileged scaffold” in the field of drug development. Various drugs consisting of isatin core have been shown to have pronounced therapeutic effects on several cancers as they have prophylactic role towards free radicals that cause cancer. This report highlights the most recent advances from the past four years in the development of isatin based drugs against several human cancer cell lines such as MCF-7 (breast cancer cell line), A-549 (lung cancer cell line), Hep-G2 (liver cancer cell line) and some other cell lines, respectively.

An α-C–H oxygenation of amides using Togni reagent II and an umpolung strategy is reported. α-Benzoyloxy amides were prepared in moderate-to-high yields from tertiary amides under mild and catalyst-free reaction conditions. All reagents are commercially available, easy to use, and compatible with various functional groups and rings. α-Benzoyloxy amides could be easily transformed into the corresponding α-hydroxy amides in almost quantitative yields. This transformation has significant potential for the synthesis of important compounds in pharmaceutical and agricultural fields.

OfChtI and OfChi-h are ideal targets for developing agricultural inhibitors against Ostrinia furnacalis. In order to further confirm the importance of conjugated systems in rhodanine derivatives, sixteen novel 1,4-benzodioxane-tethered-rhodanine derivatives were designed and synthesized with or without C=C double bond of 5-alkenyl rhodanine skeleton. Among them, compounds 3a–3h, with preserved 5-alkenyl rhodanine skeleton, all exhibited much better inhibitory activities against both OfChtI and OfChi-h, compared to that of the corresponding reduced compounds 4a–4h without its C=C double bond. The inhibitory mechanism demonstrated that the 5-alkenyl rhodanine conjugated plane was conducive to improving the binding affinity with both two chitinases. Compound 3g was identified as the most potential dual-chitinases inhibitor against OfChtI (K_i = 2.57 μM) and OfChi-h (K_i = 2.03 μM). The bioassay study also indicated that compound 3g displayed the best insecticidal activity against O. furnacalis and distinctive sublethal effect in regulating its growth and development. These 1,4-benzodioxane-tethered-rhodanine derivatives deserved further investigation as novel dual-chitinases inhibitor candidates in the control of O. furnacalis.

A series of tetrahydrobenzo[cd]indole derivatives was synthesized by condensation of a fungal metabolite hyphodermin A, a naphtho[1,2-c]furan-3,9-dione derivative, and various anilines in methanol. Using this approach, ten analogs (3a–3j) were synthesized and tested as inhibitors against glycogen phosphorylase (GP). While compounds 3e and 3i bearing hydrophobic bromo and trifluoromethyl groups showed moderated inhibition (K_i = 32.3–57.4 μΜ), compound 3g with hydroxy group had the most potent activity with a K_i value of 7.9 ± 0.7 μΜ against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb-3g complexes revealed that this inhibitor binds at a subsite within the indole binding site of GP which has not been previously observed to bind ligands.

The use of natural plants as powerful sources for the treatment of chronic illnesses has drawn more attention from researchers to herbal remedies. Silybum marianum, a naturally occurring plant, is the source of silymarin, a flavonolignan which is used to guard against a range of illnesses in both clinical and experimental contexts. Silymarin is easily absorbed and metabolised in phases I and II, according to its pharmacokinetics. Phase II is the site of its conjugation, and it is finally excreted in bile and urine. In a variety of tissues, the primary active components, silymarin and silibinin, provide protection against cancer. Silibinin has been shown to have anti-inflammatory, anti-angiogenic, antioxidant, and anti-metastatic properties. This further helps to block many oncogenic pathways from being activated such as NF-κB, Wnt/β-catenin, PI3K/Akt, and MAPK pathways. Hence, silibinin helps in preventing proliferation of the tumor cells, initiating the cell cycle arrest, and induce cancer cells to die. This review gives the thorough analysis of silibinin in distinct types of cancer such as lung, liver, breast, bladder, prostate, skin and ovarian cancer.

Trypanosomiasis, which is brought on by trypanosome parasites, is still a serious but often ignored health issue, especially in nations with limited resources. It is necessary to create novel, safe, effective, and alternative anti-trypanosomal chemical substances because current treatments have significant adverse reactions, low potency, high levels of toxicity, and drug resistance. Drug regimens that constitute the fundamental basis of contemporary pharmacological therapy have been largely derived from substances that are natural. Plants are mainly revered as ancient medicines worldwide and have contributed to the development of important pharmaceuticals for widespread medical conditions. An innovative approach for obtaining a reliable and potentially rich source of treatment against a variety of infectious diseases has been demonstrated by plant-focused research. This review discusses various phytoconstituents that have been utilized in the treatment of trypanosomiasis. Various recent and earlier studies that have investigated the in-vitro or in-vivo potential of medicinal plants for anti-trypanosomal properties have been discussed. The presence of bioactive plant-based compounds like quinones, flavonoids, phenols, etc., in the essential oils and unrefined extracts of various medicinal herbs, is part of a significant approach associated with the development of novel therapeutics. These substances have been found to be a reliable source of medicinal substances to aid in the treatment of trypanosomiasis. This review emphasizes the use of various plants with their phytoconstituents as an avenue of novel and potent medications against Trypanosomiasis. It discusses various studies of trypanocidal properties of alkaloids, essential oils, phenols, flavonoids, etc., that have been widely utilized against Trypanosoma. The results from both in vitro and in vivo studies demonstrate these natural compounds’ potential as therapeutics for the management of Trypanosoma infections.

Graphical abstract

The Graphical abstract summarizes various phytochemicals that have been discussed in the manuscript along with various studies against Trypanosoma infection.