Medicinal Chemistry最新文献

Background: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section). Some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals.

Objective: To perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America.

Methods: ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/ geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the opensource software SwissADME and pkCSM-pharmacokinetics.

Results: Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonicin A seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds.

Conclusion: Dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies.

Cancer is an uncontrolled, abnormal growth of cells and the second cause of death after cardiovascular disease. At present, chemotherapy and related drugs have three major categories. All three have characteristic action and toxicity levels of antitumor activity. Due to indications of unwanted side effects, the exploration of novel and selective anticancer agents is crucially required. Heterocyclic compounds have always played a major role in research for new drug discovery and development. 1,3,4-oxadiazole derivatives are heterocyclic isomers having pharmacological properties and play an important role as antiproliferative agents. The present review summarizes anticancer activities of 1,3,4-oxadiazole derivatives against different cell lines, such as HCT-116, MCF-7, HeLa, SMMC-7721, and A549. The results showed that 1,3,4-oxadiazole and its derivatives have the potential to play a major role as an anticancer agent with fewer side effects.

Cancer is a deadly human disease on the rise due to changes in lifestyle, nutrition, and global warming. Cancer is characterized by uncontrolled, disordered, and undesired cell division. About 60% of cancer medicines approved by the FDA are made from natural ingredients. Intensive efforts over the last decade to better understand the vast chemical diversity provided by marine life have resulted in an intriguing "marine pipeline" of potential anticancer clinical and preclinical treatments. The molecular targets of marine products as anticancer drugs, as well as different reported compounds acting on distinct targets, are the topic of this review.

Background: The carbonic anhydrases (CAs) which are found in most living organisms is a member of the zinc-containing metalloenzyme family. The abnormal levels and activities are frequently associated with various diseases therefore CAs have become an attractive target for the design of inhibitors or activators that can be used in the treatment of those diseases.

Methods: Herein, we have designed and synthesized new benzimidazole-hydrazone derivatives to investigate the effects of these synthesized compounds on CA isoenzymes. Chemical structures of synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay.

Results: These compounds have IC₅₀ values of 5.156-1.684 μM (hCA I) and 4.334-2.188 μM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 5.44 ± 0.14 μM-0.299 ± 0.01 μM (hCA I) and 3.699 ± 0.041 μM-1.507 ± 0.01 μM (hCA II). The synthetic compounds displayed inhibitory action comparable to that of the clinically utilized reference substance, acetazolamide. According to this, compound 3p was the most effective molecule with an IC₅₀ value of 1.684 μM. Accordingly, the type of inhibition was noncompetitive and the Ki value was 0.299 ± 0.01 μM.

Conclusion: According to the in vitro test results, detailed protein-ligand interactions of the compound 3p, which is more active against hCA I than standard azithromycin (AZM), were analyzed. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Background: 1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which makes it applicable to the design and development of anti-osteosarcoma drugs.

Objective: The aim of this study is to establish a satisfactory model based on 1, 8-naphthimide derivatives that makes reliable prediction as DNA-targeted chemotherapy agents for osteosarcoma.

Methods: All compounds are constructed using ChemDraw software and subsequently optimized using Sybyl software. COMSIA method is used to construct QSAR model with the optimized compound in Sybyl software package. A series of new 1, 8-naphthalimide derivatives are designed and their IC₅₀ values are predicted using the QSAR model. Finally, the newly designed compounds are screened according to IC₅₀ values, and molecular docking experiments are conducted on the top ten compounds of IC₅₀.

Results: The COMSIA model shows that q² is 0.529 and the optimum number of components is 6. The model has a high r² value of 0.993 and a low SEE of 0.033, with the F value and the r² predicted to be 495.841 and 0.996 respectively. The statistical results and verification results of the model are satisfactory. In addition, analyzing the contour maps is conducive to finding the structural requirements.

Conclusion: The results of this study can provide guidance for medical chemists and other related workers to develop targeted chemotherapy drugs for osteosarcoma.

In the last decade, quinazoline has been one of the most explored scaffolds by researchers around the globe in medicinal chemistry. Its unique structural features provide a wide range of substitutions for nitrogen and carbonyl groups. In the current situation of COVID-19, hydroxychloroquine, an antimalarial drug of the quinoline category, was used for the treatment of severe infections. Various substitution patterns, hybrids, and conjugates of quinazoline have been developed and studied for various pharmacological activities like anticancer, anti-inflammatory, antimalarial, antitubercular, etc. The scaffold can be considered a potential molecule for various pharmacological activities, especially antimicrobial and anti-hypertensive. This review article aims to study the physicochemical properties, chemistry, and pharmacological profile of quinazoline.

Background: Inflammation is a protective biological process, but under extreme conditions, it can become highly dreadful to the body. Antioxidant and anti-inflammatory agents treat similar disease conditions as inflammation and oxidative stress commonly follow similar causative pathways.

Objective: The goal of this study was to synthesize N-substituted indole derivatives with different heterocyclic moieties through propyl linker with the aim of getting highly potent anti-inflammatory and antioxidant agents.

Methods: Synthesized compounds were analyzed by analytical techniques such as IR, ¹H NMR, ¹³C NMR spectra, and mass spectrometry. Molecular docking and ADME calculation were employed on synthesized compounds to estimate their COX-2 enzyme inhibition and drug like properties, respectively. Antioxidant activity was evaluated by the DPPH assay and the reducing power assay. Selected derivatives were evaluated for anti-inflammatory activity at an acute (carrageenan-induced paw edema method) and chronic level (formalin-induced inflammation method) using indomethacin as a standard drug.

Results: Herein, twelve indole derivatives (11a-c, 12a-c, 13a-c, and 14a-c) were synthesized. Among all, compound 12c was found to be the best inhibitor of the COX-2 enzyme as it displayed good interaction energy. Zero violations of Lipinski's rule were found in the ADME investigation, confirming the drug-like qualities of synthesized compounds. The compounds 11a and 12c were found to be the most potent as compared with standard ascorbic acid in antioxidant evaluation. From the collected results, compounds 12c and 13b were the most potent against acute and chronic inflammation.

Conclusion: The novel synthetic indole derivatives could act as potent leads for the development of novel antioxidant and anti-inflammatory agents.

Background: Some species of Marine bacteria pose great risks to human and mariculture organisms. Meanwhile, Vibrio harveyi and Vibrio parahaemolyticus strains have acquired resistance to many antibiotics.

Objective: A novel series of erythromycin 9-acylhydrazone derivatives were synthesized and evaluated for their in vitro antibacterial activity against marine pathogens.

Methods: The site-selective N-acylation of erythromycin hydrazone was achieved using acid chloride/ triethylamine in methanol as the reaction system. All the synthesized target compounds were evaluated for their antibacterial activity by determination of minimum inhibitory concentrations (MICs) using the broth microdilution method.

Results: All the tested acylhydrazone compounds showed moderate to high activity with MIC value 0.125-1 μg/mL against Vibrio parahaemolyticus and Vibrio harveyi.

Conclusion: The introduction of the acylhydrazone moiety at the C-9 position of erythromycin improved its activity against the above-mentioned marine bacteria strains.

Background: The structure modification of steroids is commonly used to change the biological activity of steroids in medicinal chemistry. In recent years, it has been found that some derivatives derived from the structural modification of cholesterol display good inhibitory activity against tumor cell proliferation in vitro.

Methods: Using cholesterol as the starting material, different types of B-norcholesterol-6-amide derivatives were synthesized by the reaction of 6-carboxyl-B-norcholesterol with different alkyl amines or 6-amino-B-norcholesterol with different acyl chlorides. The inhibitory activity of compounds on the proliferation of tumor cell lines was investigated by the MTT method.

Results: The results showed that the B-norcholesterol-6-amide compounds displayed distinct cytotoxicity against Sk-Ov-3 cells but caused no obvious damage against HEK-293T cells. Additionally, the steroidal amide derivatives formed from 6-amino-B-norcholesterol showed stronger cytotoxicity than those produced from 6-carboxyl-B-norcholesterol. Specially, compounds with chloroalkyl structure displayed significant inhibitory activity against all tumor cells tested. Among them, compounds 19-21 showed cytotoxicity like 2-methoxyestradiol as a positive control, and the IC₅₀ value of compound 20 on HeLa cells was 3.9 μM.

Conclusion: After introducing chloroalkyl acyl groups into 6-position of 6-amino-B-norcholesterol, the cytotoxicity of resulting B-norcholesterol-6-amide compounds can be greatly enhanced.

SARS-CoV-2 was first discovered in Wuhan in late 2019 and has since spread over the world, resulting in the present epidemic. Because targeted therapeutics are unavailable, scientists have the opportunity to discover new drugs or vaccines to counter COVID-19, and therefore a number of synthetic bioactive compounds are now being tested in clinical studies. Due to its broad therapeutic spectrum and low adverse effects, medicinal herbs have been used as traditional healing medication in those countries for ages. Due to a lack of synthetic bioactive antiviral medications, pharmaceutical and alternative therapies have been developed using a variety of herbal compositions. Due to the widespread availability of herbal and dietary products worldwide, people frequently use them. Notably, the majority of Bangladeshi people continue to use a variety of natural plants and herbs to treat various types of diseases. This review article discusses how previous research has shown that some herbs in Bangladesh have immunomodulatory and antiviral effects and how their active ingredients have been gathered. Even though FDA-approved medications and vaccines are available for the treatment of COVID-19, the purpose is to encourage the use of herbal medicine as immunomodulators and vaccine adjuvants for the treatment of COVID-19 prevention.