Medicinal Chemistry最新文献

Dementia with Lewy Bodies is a neurodegenerative disorder characterised by abnormal α-Synuclein aggregate accumulation in Lewy Bodies and Lewy Neurites and the most common form of dementia after Alzheimer's disease. The presynaptic protein alpha-synuclein (α-Syn) regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters in the brain. These aggregates go through a number of crucial stages, such as aggregation, oligomerization, and fibrillation. Treatment of this disorder is generally symptomatic. This necessitates the development of cutting-edge therapeutic approaches that can either stop or change the course of the diseases. Many studies have shown that α-synuclein is a significant therapeutic target and that inhibiting α-synuclein aggregation, oligomerization, and fibrillation is an important disease-modifying strategy. Since α-syn is a defining feature of Parkinson's disease, the current review provides an overview of plant phytochemicals and synthetic heterocyclic compounds that target α-syn in Parkinson's disease in order to develop new drugs for Dementia with Lewy Bodies.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), responsible for generating COVID-19, has spread worldwide and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020, being responsible for various damages to public health, social life, and the economy of countries. Its high infectivity and mutation rates have stimulated researchers and pharmaceutical companies to search for new therapies against this disease. These efforts resulted in several vaccines and the identification of Molnupiravir as an oral treatment for this disease. However, identifying new alternatives and critical information is necessary to fight against this devastating agent. The findings in recent years regarding the structure and biochemistry of SARS-CoV2 are remarkable. In anti-CoV drug discovery, various targets, such as structural, non-structural, and hostrelated proteins are explored. In fact, 3CL^pro is the most used among non-structural proteins since this protease cleaves peptide sequences after the glutamine residue, and no human protease has this function. This makes this macromolecule an excellent drug target for discovering new compounds. Another promising target is the transmembrane protease serine 2 (TMPRSS2). Recent studies point to TMPRSS2 as one of the main targets responsible for viral entry related to the cleavage of the S protein. Similar to cathepsins, TMPRSS2 is also responsible for cleaving the spike protein SARS-CoV2, which binds to the ACE2 receptor. Thus, TMPRSS2 is one of the targets that may represent new alternatives in treating SARS-CoV2. In this context, would discovering a multitarget inhibitor be the new strategy in searching for drugs against SARS-CoV2? For many years, new drug discovery was based on the "one drug, one target" premise, where the biological action is related to interactions with only one biological target. However, this paradigm has been overcome as new evidence of multiple mechanisms of action for a single drug. Finally, this review will present a perspective on drug design based on a multitarget strategy against 3CL^pro and TMPRSS2. We hope to provide new horizons for researchers worldwide searching for more effective drugs against this devastating agent.

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.

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: 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.

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: 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.

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.