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  • Open access
  • 57 Reads
N-benzyl derivatives of 2-amino-8-methoxy-4H-chromene-3-carbonitrile: synthesis via reductive amination, in silico ADME profiling & exploration of their effects against protein kinases.
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The synthesis of 2-benzylamino-8-methoxy-4H-chromene-3-carbonitriles 7(a-e) has been realized in four steps, via reductive amination from the 2-amino-8-methoxy-4H-chromene-3-carbonitrile 4 as key intermediate platform with para- and meta-substituted benzaldehydes 5(a-e), in good overall yields. The physicochemical properties of 7(a-e) and also their aldimines 6(a-e) precursors have been determined using the Swiss ADME server platform according to the Lipinski’s descriptors. Biological assays with a panel of six protein kinases such as HsCDK5-p25, HsCDK9/cyclin T, HsPim1, HsHaspin, SscGSK-3a/b and SscCK1d/e showed that aldimines 6(a,b) and 6e are potentially interesting because they showed good percentage of residual activities against HsPim1 and HsHaspin.

  • Open access
  • 48 Reads
Optimization of Radiolabeling methods of His-tagged single-chain antibody fragments (scFvs) with technetium tricarbonyl 99mTc(CO)3 as a molecular imaging agent
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Single-chain antibody fragments (scFvs) are considered more valuable agents for clinical imaging compared with parent antibodies due to their rapid tumor uptake and high tumor-to-background ratios at early times.

A number of studies reported that biomolecules can be radiolabeled with 99mTc in a high yield using indirect labeling techniques or non-site-specific conjugations, but these approaches can reduce their biological activities. His-tags are specific sites for radiolabeling of scFvs with 99mTc-tricarbonyl ([99mTc(CO)3]+). According to the reported studies, radiolabeling efficiency of His-tag-containing biomolecules varies unpredictably and depends on a series of various factors including the structure of the biomolecule and the conditions of radiolabeling.

Therefore, in this study, we tried to radiolabel two His-tagged scFvs with precursor complex of 99mTc(CO)3 and evaluate their radiolabeling efficiencies in different conditions including type of buffer, volume, ionic strength, pH, the concentration of antibody, and activity, temperature, and time using Thin-layer chromatography (TLC) and gamma counter.

His-tagged scFvs were radiolabeled with [99mTc(CO)3] + in 100% radiochemical purity at a range of 480-600 µCi/µg for 2 h at 50°C. We demonstrated that the radiochemical purity of radiolabeled His-tagged scFvs increases with higher [99mTc(CO)3]+ activity, and antibody concentrations in a smaller volume, increasing the temperature and pH of the reaction medium. Moreover, the radiolabeled His-tagged scFvs showed high stability for 24 h in the reaction medium. In the present study, the optimal and efficient radiolabelling of His-tagged scFvs successfully obtained that they can be used as potential agents for in vivo imaging.

  • Open access
  • 51 Reads
Molecular Docking Studies of 1,3,4-Thiadiazole Amidoalkyl Derivatives as Potential Inhibitors of Dihydrofolate Reductase.

Derivatives of 1,3,4-thiadiazole are of great interest to medicine and pharmacy as potential drug substances. Recently, a large number of works have appeared on the inhibition of dihydrofolate reductase (DHFR) by representatives of this class of compounds, which makes them promising antitumor agents. In this work, we carried out molecular docking studies of amidoalkyl derivatives of 1,3,4-thiadiazole - N-(2,2,2-trichloro-1-((5-aryl-1,3,4-thiadiazol-2-yl)amino)ethyl)carboxamides and N-(2,2,2-trichloro-1-((5-(arylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)carboxamides with DHFR. The AutoDock Vina program based on the PyRx 0.8 platform was used for docking. Before docking, the enzyme structure (PDB ID: 1DLS) was prepared using the Chimera 1.14 program, and the structures of potential inhibitors and reference preparations were optimized by the PM3 method in the ArgusLab 4.0.1 program. According to the results of molecular docking, the analyzed compounds effectively interact with the active site of DHFR. It is shown that the introduction of an NH group between the 1,3,4-thiadiazole and aromatic rings leads to stronger binding of ligands to DHFR. Based on the results of molecular docking, hit compounds were selected - 4-methyl-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide and 4-methyl-N-(2,2,2-trichloro-1-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide, which are superior to the reference compounds according to the strength of the formed complex.

  • Open access
  • 35 Reads
The journey towards solubility assessment of small molecules using HPLC-DAD
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Through the process of developing bioactive small molecules, solubility determination is a crucial step. Many research papers treating problems related to solubility are published, but none of them fully describes the methods and steps for solubility assessment. In addition, in silico prediction tools and databases, such as SwissADME, ACD/Percepta, DrugBank and many others offer the possibility to have approximative solubility values based on the structure of the molecule. Although, significant differences can be observed depending on the database and the conditions of the experiment: solvent, pH, temperature… etc. The lack of data can be a barrier to obtaining details on solubility measurement methods. This presentation aims to describe, step by step, the journey of theophylline solubility determination using HPLC-DAD.

  • Open access
  • 38 Reads
Modeling of new VHR inhibitors based on 4H-1,3,5-oxadiazine derivatives.

Vaccinia H1-related phosphatase (VHR) is a dual-specific phosphatase that is a promising potential target for the treatment of many human diseases. In this work, we have proposed a series of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines as potential VHR inhibitors. The SuperPred online server predicts VHR inhibition for the studied compounds with a probability of 88.88-98.51%. To establish the efficiency of binding of 4H-1,3,5-oxadiazine derivatives to the active site of VHR (PDB ID: 3F81) in the AutoDock Vina program, we have carried out molecular docking studies. According to its results, the studied compounds effectively interact with the hydrophobic region of the VHR active site due to aromatic rings and the trichloromethyl group, but the polar catalytic cavity is not involved, and therefore inhibition cannot be effective. In this regard, we have built a number of model compounds containing a sulfate group and its derivatives (methyl ester and amide) in the para-position of the arylamine fragment. According to the results of molecular docking, these compounds effectively bind to the polar catalytic cavity of the enzyme due to hydrogen bonds, but due to the relative rigidity of their molecules, hydrophobic interactions are not fully realized. Therefore, in these model compounds between the arylamine fragment and the sulfo group, we introduced a spacer with a length of one to three methylene groups. Hit compounds have been selected - 2-(4-((6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-yl)amino)phenyl)ethane-1-sulfonic acid and its amide.

  • Open access
  • 47 Reads
Hybridization of Fluoroquinolones as a Promising Pathway towards New Antibiotics

Current situation in medicine and pharmacy still requires time and effort of medicinal chemists who must develop new synthetic approaches and create promising molecules that can turn into novel antimicrobials. Due to the problem of resistance to well-known antibiotics combined with the occurrence of new diseases that we observe, we can be sure that these researches are going to be in demand.

However, not always searching for a totally new molecule seems to be a good idea. Structural modification and hybridization of once efficient agents is also logical and actually has already provided us with many generations of antibiotics. Therefore, our scientific team has been working with fluoroquinolones aiming to conduct docking studies, modify them, and then study biological activity of the obtained compounds.

At the first stage of the research we conducted docking studies and then started to work on ciprofloxacin and norfloxacin, modifying only their C-7 position. Introduction of 1,2,3-triazole moiety as a result of a convenient synthetic procedure led to new molecules for which moderate antimicrobial and antifungal activities was revealed. Furthermore, C-3 position was modified with arylsulfonyl moiety with parallel modifications of N-1 and C-7. For now, synthetic procedures are developed for similar transformation and biological activity of the obtained compounds is under study.

  • Open access
  • 59 Reads
Interaction between pimethixene and human serum albumin

Albumin, is the highly abundant protein in the plasma. The main function of protein is delivery various endogenous (fatty acid, vitamins, hormones) and exogenous compounds such as drugs. Further, human serum albumin has a very important role in distribution, free concentration and effectiveness of these compounds.

Pimethixene belongs to the group of antihistamines characterized by sedative and antitussive properties. It has shown remarkable ability to bind to receptors such as serotonin 5-HT2A and 2B, histamine H1 and muscarinic acetylcholine M2. Moreover, oral pimethixene is used to calm dry and irritating coughs in children. However, binding constants of pimetixene for human serum albumin, as the most abundant serum transport protein, have not been determined so far.

Accordingly, in the current study explored the interactions between pimethixene and human serum albumin (HSA) by the spectroscopic measurements (fluorescence spectroscopy and circular dichroism) and molecular docking method.

  • Open access
  • 51 Reads
Introducing novel ERK2 Inhibitors via de novo drug design supported by Molecular Docking, Physicochemical properties, and Molecular Dynamics Study

Extracellular signal-regulated kinase 1/2 (ERK1/2) is a serine/threonine protein kinase in eukaryotic cells and belongs to the mitogen-activated protein kinase (MAPK) family. ERK1/2 is essential for signaling from surface receptors to the nucleus. Activated ERK1/2 phosphorylates substrates in the nucleus or cytoplasm, causing certain proteins to be expressed or activated, regulating cell proliferation, differentiation, death, and other functions. ERK1/2 is abundantly expressed in several forms of ischemia-reperfusion injury (IRI). Caffeic acid (3,4-dihydroxy cinnamic acid), as previously reported, interacted directly with ERK1/2 and reduced its actions in vitro. It is the most abundant phenolic component found in coffee. Moreover, it is reported to have a variety of pharmacologic effects, including anti-inflammatory, immunomodulatory, antioxidant, and anticancer effects. In the present study, we employ a deep learning protocol to generate novel and effective anti-ERK1/2 drugs by modifying the chemical structure of caffeic acid, aiming to improve its inhibition performance. Conventional methods in the drug discovery and development process can take several years, and the cost of bringing a novel drug to market can be around two billion dollars. Instead of all these efforts, computer-aided drug design (CADD) can be an effective, rapid, and cost-efficient method to design novel drugs. In the current study, a molecular docking as well as a molecular dynamics study will be executed to explore the effectiveness of the generated drugs. To get a deeper insight into the potency of the studied inhibitors, drug-likeness analysis will be applied to check the bioavailability of the best-ranked drugs.

  • Open access
  • 31 Reads
The iridoids of in vitro propagated Nepeta cyrenaica Quézel & Zaffran
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Nepeta cyrenaica Quézel & Zaffran (Lamiaceae), an endemic species of the Libyan flora, has been scarcely explored till now. Since Nepeta species are proved as pharmacologically active plants rich in iridoid monoterpenes, this study was aimed to quantify the iridoids present in different extracts of in vitro propagated N. cyrenaica. The seeds collected from natural habitat were germinated. One node stem explants of 5 weeks old plants were used for plant micropropagation. After several cycles, the shoots were harvested. The extraction was done using maceration procedure by dichloromehane, methanol, 96% ethanol, and hot distilled water. Subsequently, the extracts were subjected to UHPLC/(±)HESI-MS2 analysis of iridoids. Two iridoids were identified and quantified, namely epideoxyloganic acid and nepetalactol, as well as their precursor 8-oxogeranial. Iridoid glucoside epideoxyloganic acid was the most abundant in the methanolic and ethanolic extracts (1255.37 and 1262.78 µg/100g dry extract), followed by aqueous extract. On the other hand, 8-oxogeranial and nepetalactol reached maximal amounts in the dichloromethane extract (476.80 and 1039.52 µg/100g dry extract, respectively). The results of this study indicate that high antioxidant and enzyme-inhibiting effects of dichloromethane extract confirmed in our previous study could be attributed to its iridoid content, which was particularly high due to the low polarity of this extraction solvent. In conclusion, endemic N. cyrenaica could be efficiently propagated in vitro as a iridoid-rich plant with great biological potential.

  • Open access
  • 68 Reads
Molecular modeling and synthesis of new HIV latency-reversing agents targeting the lymphatic system

Background: During the HIV infection, a small amount of the virus remains in a latent state, forming a viral reservoir in places with limited access to drugs such as lymph nodes. HIV latency reversing agents, as HDAC inhibitors, have been used in the “kick and kill” strategy aiming to reactivate the latent virus and its subsequent elimination. Combining these compounds with a lipophilic group may promote an increase in lipophilicity and improve the bioavailability. In order to target these compounds to lymphatic system, we described the design, synthesis and evaluation of pro-drugs of HDAC-3 inhibitors. Methods: In silico studies were performed using the molecular modelling Maestro by Schrödinger environment using HDAC-3 (PDB: 4A69). All compounds were prepared through divergent synthesis. The reactions consisted of NH2 protection in 5-fluoro 2-nitroaniline reagent using di-tert-butyl dicarbonate, reduction of the NO2 group with Fe and NH4Cl/MeOH and coupling reactions using HATU/DIPEA or oxalyl chloride with palmitic and α-linolenic acid. LogP values ​​were determined by HPLC-UV (C18, MeOH:H2O). Results: Docking simulation suggests that all compounds are able to interact with HDAC-3, with docking score values of -6.078 to -8.369. Four compounds were synthesized at global yields ranging from 21-68%. All structures were characterized by analytical methods. LogP values were determined ranging from 4.89-6.5. Conclusions: Pro-drug compounds were designed and synthesized. The results of in silico studies and experimental LogP justify that these compounds can be targeted to the lymphatic system, to act as HDAC-3 inhibitors.