Potent Derivatives Research Articles

Scalarane Sesterterpenoids Isolated from the Marine Sponge Hyrtios erectus and their Cytotoxicity.

Eighteen scalarane sesterterpenoids (1–18), including eight new derivatives (1–8), were isolated from the sponge Hyrtios erectus (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (1–6) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC50 0.18 and 0.13 μΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC50 value of 20.0 μΜ. The compounds containing a γ-hydroxybutenolide moiety (1–3, 10, 12) showed cytotoxicity, with IC50 values ranging from 24.3 to 29.9 μΜ, and the most potent derivative was heteronemin (16). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure–activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity

Nineteen new quinazolin-4(3H)-one derivatives 3a–g and 6a–l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI50 = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59–9.55 µM). Compound 6d potently inhibited EGFR with IC50 = 0.069 ± 0.004 µM in comparison to erlotinib with IC50 value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.

Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI50 values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI50 value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC50 values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC50 = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC50 values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC50 = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.

3,5-Dinitrobenzoate and 3,5-Dinitrobenzamide Derivatives: Mechanistic, Antifungal, and In Silico Studies

Fungal infections, including those caused by Candida spp., are recognized in immunocompromised individuals for their high rates of morbidity and mortality. Microorganism resistance to conventional drugs compromises treatment effectiveness and yet also reveals the need to develop new drugs. In many compounds, nitro groups contribute to antimicrobial activity; thus, the inhibitory activity of a collection of twenty esters and amides (derived from 3,5-dinitrobenzoic acid) against Candida spp. was elucidated using microdilution methods to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicide Concentration (MFC), as well as probable mechanisms of action. The structures of the synthesized compounds were characterized by FTIR spectroscopy, 1H-NMR, 13C NMR, and HRMS. Of the tested derivatives, ten presented fungicidal activity against at least one of the tested strains. Ethyl 3,5-dinitrobenzoate (2) exhibited the most potent antifungal activity against Candida albicans (MIC = 125 µg/mL; 0.52 mM), Candida krusei (MIC = 100 µg/mL; 4.16 mM), and Candida tropicalis (MIC = 500 µg/ml; 2.08 mM). The structure of the second most potent derivative (propyl 3,5-dinitrobenzoate (3) reveals that esters with short alkyl side chains exhibit better biological activity profiles. Compounds 2 and 3 presented a mechanism of action involving the fungal cell membrane. Though compound 2 modeling against C. albicans revealed a multitarget antifungal mechanism of action, involving various cellular processes, interference in the synthesis of ergosterol was observed. Our results demonstrate that certain ester derivatives containing aromatic ring nitro groups may be useful in the search for new antifungal drugs.

Annotated Review on Various Biological Activities of Quinoline Molecule

Quinoline or Benzopyridine moiety remained an attraction among researchers in the 21st century. Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. This moiety is considered a biologically important active source that possesses all types of medicinal potentials due to its simple chemistry, ease of synthesis, and a wide variety of numerous biological potentials in both natural and synthetic derivatives such as antimalarial, antibacterial, anti-inflammatory, anti-arrhythmic, anti-anginal, antihypertensive, anti-depressant, anti-convulsant. This pharmacological diversity of quinoline has attracted researchers to explore this moiety by making modifications at various possible positions. In the present review, we are outlining the potential of quinoline as an antimalarial, anticancer, anti-inflammatory, and antibacterial agent. Furthermore, by attaining the knowledge of molecular targets, structural insights, and SARs, this review may be supportive for medicinal chemists to design more potent, safe, selective, and cost-effective quinoline derivatives for various biological properties.

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 μM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 μM), 8f (R = 4-OH, IC50 = 0.072 μM), and 19e (IC50 = 0.19 μM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 μM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining.

Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6-diamino-2-mercaptopyrimidin-4-ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27-fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV-dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double-strand breaks inside cells, and improved anti-cancer potential when combined with γ-radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics.

Synthesis, biological evaluation and computational investigations of S-benzyl dithiocarbamates as the cholinesterase and monoamine oxidase inhibitors

The current study was aimed to identify the selective and multi-targeted inhibitors of cholinesterase and monoamine oxidase enzymes. For this purpose, a novel class of multi-targeted compounds i.e., S-benzyl dithiocarbamates (1-30) was synthesized via a single pot reaction and the structures were characterized via NMR (1H and 13C), FT-IR and high-resolution mass spectrometry (HRMS). Moreover, the purity of the final products was determined using thin-layer chromatography (TLC). The compounds were evaluated for their inhibitory potential against cholinesterases (ChE) and monoamine oxidases (MAO). Among all derivatives, compound 5 (2-(trifluoromethyl) benzyl azepane-1-carbodithioate) depicted the maximum inhibition of AChE and BChE enzyme with an IC50 value of 4.37±0.94 and 14.9±1.11, respectively. The derivative 11, expressed maximum inhibition of MAO-A and MAO-B with an IC50 value of 1.14±0.03 and 1.01±0.16 µM, respectively. Whereas, compound 16 exhibited maximum inhibitory potential against all four targeted enzymes i.e., AChE, BChE, MAO-A and MAO-B with an IC50 value of 1.39±0.07 µg/ mL, 1.52±0.14 µg/ mL, 44.9±1.54 µM and 2.85±0.21 µM, respectively. The chemical reactivity profile of the potent derivatives were evaluated through density functional theory studies (DFT) where it was found that compound 5, 6 and 11 possessed reactive character due to narrow LUMO/HOMO energy gap. In addition, Molecular docking studies revealed excellent docking scores and produced sable protein-ligand complexes. The stability of protein-ligand complex was affirmed by molecular dynamic simulations which revealed stable and equilibrated trajectories of simulated complexes. The findings of in-vitro and in-silico studies suggested compound 16 as a promising multi-targeted compound that can be act as lead molecule for the treatment of AD.

Novel 2-substituted thioquinazoline-benzenesulfonamide derivatives as carbonic anhydrase inhibitors with potential anticancer activity.

A novel series of 2-thioquinazoline-benzenesulfonamide hybrids were designed as carbonic anhydrase (CA) inhibitors. The design approach relies on molecular hybridization between the benzenesulfonamide scaffold as a Zn2+ binding group and 2-substituted thioquinazolines as a tail. Assaying the thioquinazoline-benzenesulfonamide conjugates against four different CA isoforms revealed that compounds 12f and 12p are the most potent derivatives. They exhibit Ki = 0.09 and 0.05 µM on CA II, 0.32 and 0.47 µM on CA IX, and 0.58 and 0.46 µM on CA XII, respectively. In addition, 12p demonstrated high selectivity for CA II over CA I with selectivity index (SI) = 92, and slightly higher specificity for CA II over CA IX and CA XII with SI = 9.40 and 9.20, respectively. The synthesized compounds were screened for their cytotoxic activity at 10 µM concentration and derivatives 12o, 12n, and 12f turned out to be the most potent ones from the synthesized series; they exhibit mean growth inhibition % values of 89.38%, 58.75%, and 54.71%, respectively, while 12p demonstrated moderate activity against the NCI cancer cell lines, with mean growth inhibition % = 29.62%. The analysis of the MCF-7 cell cycle after treatment with 5.0 µM of 12f displayed that it arrests the cell cycle at the G2/M phase. Molecular docking simulation of the thioquinazoline-benzenesulfonamide hybrids in the CA II active site rationalized the potent activity to the settlement of the sulfonamide moiety at the depth of the CA II active site and its stabilization by performing the important interactions with the Zn2+ ion as well as with the key amino acids Thr199 and/or Thr200, while the thioquinazoline moiety with different (un)substituted phenyl tails is stabilized by the formation of various hydrogen bonding and hydrophobic interactions with the surrounding amino acids in the binding site.

Tetracyclines: four rings to rule infections through resistance and disease tolerance.

Several classes of antibiotics have long been known for protective properties that cannot be explained through their direct antimicrobial effects. However, the molecular bases of these beneficial roles have been elusive. In this issue of the JCI, Mottis et al. report that tetracyclines induced disease tolerance against influenza virus infection, expanding their protection potential beyond resistance and disease tolerance against bacterial infections. The authors dissociated tetracycline’s disease-resistance properties from its disease-tolerance properties by identifying potent tetracycline derivatives with minimal antimicrobial activity but increased capacity to induce an adaptive mitochondrial stress response that initiated disease tolerance mechanisms. These findings have potential clinical applications in viral infections.

Synthesis and biological evaluation of coumarin derivatives containing oxime ester as α-glucosidase inhibitors

In this study, potent coumarin derivatives containing oxime ester 1 ∼ 28 as α-glucosidase inhibitors were developed through a stepwise structure optimization, and the structure activity relationship was uncovered. Among them, compound 20 exhibited outstanding α-glucosidase inhibitory activity with IC 50 of 2.54 ± 0.04 μM compared to 640.57 ± 1.13 μM of Acarbose. Kinetic study ascertained that compound 20 was a reversible and uncompetitive α-glucosidase inhibitor. 3D fluorescence results showed that the interaction of compound 20 with α-glucosidase caused the changes of microenvironments and polypeptide backbone structure of α-glucosidase. CD spectra results revealed that compound 20 decreased the α-helix content and increased the β-sheet content. Molecular docking analysis indicated that compound 20 well located into the active site and mainly bind with Phe157, His239, His279, Tyr71, and Arg312 to reduce the catalytic activity of α-glucosidase.

Mechanistic study of the antibacterial potential of the prenylated flavonoid auriculasin against Escherichia coli.

Bacterial resistance is spreading in an alarming manner, outpacing the rate of development of new antibacterial agents and surging the need for effective alternatives. Prenylated flavonoids are a promising class of natural antibiotics with reported activity against a wide range of resistant pathogens. Here, a large library of natural flavonoids (1718 structures) was virtually screened for potential candidates inhibiting the B-subunit of gyrase (Gyr-B). Twenty-eight candidates, predominated by prenylated flavonoids, appeared as promising hits. Six of them were selected for further in vitro antibacterial and Gyr-B enzyme inhibitory activities. Auriculasin is presented as the most potent antibacterial candidate, with a MIC ranging from 2 to 4 µg/ml against two clinically isolated multidrug-resistant Escherichia coli strains. Mechanistic antibacterial analysis revealed auriculasin inhibitory activity towards the Gyr-B enzyme on the micromolar scale (IC50 = 0.38 ± 0.15 µM). Gyr-B interaction was further detailed by conducting an isothermal titration calorimetric experiment, which revealed a competitive inhibition with a high affinity for the Gyr-B active site, achieved mostly through enthalpic interactions (ΔGbinding = -10.69 kcal/mol). Molecular modeling and physics-based simulations demonstrated the molecule's manner of fitting inside the Gyr-B active site, indicating a very potential nucleus for the future generation of more potent derivatives. To conclude, prenylated flavonoids are interesting antibacterial candidates with anti-Gyr-B mechanism of action that can be obtained from a plant-derived flavonoid.

Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors

The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 µM) relative to Lapatinib (IC50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC50 = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC50 = 17.51 and 5.56 µM, respectively) and 14c (IC50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.

Synthesis and biological evaluation of novel FiVe1 derivatives as potent and selective agents for the treatment of mesenchymal cancers

Epithelial-mesenchymal transition (EMT) endows stem cell-like properties to cancer cells. Targeting this process represents a potential therapeutic approach to overcome cancer metastasis and chemotherapy resistance. FiVe1 was identified from an EMT-based synthetic lethality screen and was found to inhibit the stem cell-like properties and proliferation of not only cancer cells undergoing EMT, but also more broadly in mesenchymal cancers that include therapeutically intractable soft tissue sarcomas. FiVe1 functions by directly binding to the type III intermediate filament protein vimentin (VIM) in a mode that induces hyperphosphorylation of Ser56, which results in selective disruption of mitosis and induced multinucleation in transformed VIM-expressing mesenchymal cancer cell types. Cell-based potency (IC50 = 1.6 μM, HT-1080 fibrosarcoma), poor solubility (<1 μM) and low oral bioavailability limits the direct application of FiVe1 as an in vivo probe or therapeutic agent. To overcome these drawbacks, we performed structure-activity relationship (SAR) studies and synthesized a set of 35 new compounds, consisting of diverse modifications of the FiVe1 scaffold. Among these compounds, 4e showed a marked improvement in potency (IC50 = 44 nM, 35-fold improvement, HT-1080) and cell type selectivity (19-fold improvement), when compared to FiVe1. Improvements in the potency of 4e, in terms of overall cytotoxicity, directly correlate with VIM Ser56 phosphorylation status and the oral bioavailability and pharmacokinetic profiles of 4e in mouse are superior to FiVe1. Successful optimization also resulted in potent and selective derivatives 11a, 11j and 11k, which exhibited superior pharmacological profiles, in terms of metabolic stability and aqueous solubility. Collectively, these optimization efforts have resulted in the development of promising FiVe1 analogs with potential applications in the treatment of mesenchymal cancers, as well as in the study of VIM-related biology.

MOLECULAR DOCKING AND COMPUTATIONAL PHARMACOKINETIC STUDY OF SOME NOVEL COUMARIN–BENZOTHIAZOLE SCHIFF’S BASE FOR ANTIMICROBIAL ACTIVITY

Objective: The present study discusses molecular docking of some novel coumarin–benzothiazole Schiff bases and the prediction of pharmacokinetic properties of potent molecules by the computational method. Methods: Five protein targets were selected for the study and their structures were taken from RCSB Protein Data Bank in PDB format. Preparation of proteins was done using Discovery Studio 2021 Client. A total of twenty derivatives were drawn using ChemDraw 20.0 and saved in Mol format. Molecular docking was performed using PyRx software. Docking results were visualized by Discovery Studio 2021 Client. The pharmacokinetic properties of the best compounds were determined using the pkCSM tool. Results: All twenty derivatives were docked against the five proteins, namely DNA Ligase (PDB ID: 3PN1), Topoisomerase (PDB ID: 3TTZ), Sterol demethylase (PDB ID: 5FSA), Enoyl-acyl-carrier protein (PDB ID: 1BVR) and Glutamate racemase (PDB ID: 5HJ7). The compound JJB18 has shown the best binding score against DNA ligase (-10.7 kcal/mol), Glutamate racemase (-8.4 kcal/mol), and Enoyl-acyl-carrier protein (-10.8 kcal/mol). Further, compound JJB19 has shown the best score for fungal sterol demethylase (-10.6 kcal/mol) and compound JJB20 towards topoisomerase (-9.4 kcal/mol) than the standard drugs. The physicochemical properties of potent derivatives were also reported. Conclusion: Molecular Docking study indicates that coumarin–benzothiazole Schiff bases may be effective inhibitors for the different microbial proteins. Additionally, in silico ADMET studies predicts drug-like features. Hence, these compounds may be considered lead molecules and further investigation of their analogues may help in the development of novel drugs for the treatment of microbial diseases.

Activation of a Bacterial Mechanosensitive Channel, MscL, Underlies the Membrane Permeabilization of Dual-Targeting Antibacterial Compounds.

Resistance to antibiotics is a serious and worsening threat to human health worldwide, and there is an urgent need to develop new antibiotics that can avert it. One possible solution is the development of compounds that possess multiple modes of action, requiring at least two mutations to acquire resistance. Compound SCH-79797 both avoids resistance and has two mechanisms of action: one inhibiting the folate pathway, and a second described as “membrane permeabilization”; however, the mechanism by which membranes from bacterial cells, but not the host, are disrupted has remained mysterious. The opening of the bacterial mechanosensitive channel of large conductance, MscL, which ordinarily serves the physiological role of osmotic emergency release valves gated by hypoosmotic shock, has been previously demonstrated to affect bacterial membrane permeabilization. MscL allows the rapid permeabilization of both ions and solutes through the opening of the largest known gated pore, which has a diameter of 30 Å. We found that SCH-79797 and IRS-16, a more potent derivative, directly bind to the MscL channel and produce membrane permeabilization as a result of its activation. These findings suggest that possessing or adding an MscL-activating component to an antibiotic compound could help to lower toxicity and evade antibiotic resistance.

4'-Iodo-α-Pyrrolidinononanophenone Provokes Differentiated SH-SY5Y Cell Apoptosis Through Downregulating Nitric Oxide Production and Bcl-2 Expression.

Abuse of pyrrolidinophenone derivatives (PPs) is known to cause severe damage to the central nervous system due to their high lipophilicity. In this study, we compared sensitivity to toxicity elicited by 4'-iodo-α-pyrrolidinononanophenone (I-α-PNP), one of the most potent cytotoxic derivatives among PPs synthesized previously, between SH-SY5Y cells differentiated by all-trans-retinoic acid (ATRA) and the undifferentiated cells, and found that the differentiated cells are more sensitive to I-α-PNP toxicity than the undifferentiated cells. Treatment with I-α-PNP elicited some apoptotic alterations (Bax expression, loss of mitrochondrial membrane potential, and activation of caspases) in the differentiated cells, whose patterns were similar to those in the undifferentiated cells. I-α-PNP treatment resulted in no significant alteration in Bcl-2 expression in the undifferentiated cells, whereas it considerably downregulated the protein expression in the differentiated cells, suggesting that the high I-α-PNP sensitivity of the differentiated cells is mainly due to downregulation of Bcl-2 expression. I-α-PNP treatment decreased nitric oxide (NO) production and neuronal NOS (nNOS) expression in the differentiated cells, and the patterns of I-α-PNP-evoked alterations in phosphorylation of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression were almost the same as that in nNOS expression. Additionally, the addition of an NO donor restored the I-α-PNP-evoked alterations in expressions of Bcl-2, BDNF, and nNOS in the differentiated cells. These findings suggest that the downregulation of Bcl-2 expression by I-α-PNP in differentiated cells is attributed to the acceleration of two negative feedback loops (nNOS/NO/CREB loop and CREB/BDNF loop) triggered by decreased NO production.

An Overview of Tetramethylpyrazine (Ligustrazine) and its Derivatives as Potent Anti-Alzheimer’s Disease Agents

Abstract:Tetramethylpyrazine (TMP), or ligustrazine, is an alkaloid isolated from the Chinese herb Ligusticum wallichii. It is known for its broad-spectrum medicinal properties against several diseases, and various studies have shown that it can modulate diverse biological targets and signaling pathways to produce neuroprotective effects, especially against Alzheimer’s disease (AD). This has attracted significant research attention evaluating TMP as a potent multitarget anti-AD agent. This review compiles the results of studies assessing the neuroprotective mechanisms exerted by TMP as well as its derivatives prepared using a multi-target-directed ligand strategy to explore its multitarget modulating properties. The present review also highlights the work done on the design, synthesis, structure-activity relationships, and mechanisms of some potent TMP derivatives that have shown promising anti-AD activities. These derivatives were designed, synthesized, and evaluated to develop anti-AD molecules with enhanced biological and pharmacokinetic activities compared to TMP. This review article paves the way for the exploration and development of TMP and TMP derivatives as an effective treatment for AD.

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies.

To discover anticancer drugs with novel structures and expand our research scope, pyrazoline derivatives (3a–3l) were designed and synthesized through cyclization of chalcones with thiosemicarbazide/semicarbazide in CH3COOH as a solvent. All newly synthesized pyrazoline derivatives were fully characterized using several spectroscopic experiments such as 1H, 13C NMR, FT-IR spectroscopy, and mass analysis. By HPLC, the purity of all analogs was found above 95% and both lead compounds (3a and 3h) were also validated by HRMS. Anticancer activity of synthesized pyrazoline derivatives (3a–3l) was investigated by the MTT assay against the human lung cancer cell (A549), human cervical cancer cell (HeLa), and human primary normal lung cells (HFL-1). Staurosporine (STS) was used as a standard drug. The anticancer results showed that two potent analogs 3a and 3h exhibit excellent activity against A549 (IC50 = 13.49 ± 0.17 and 22.54 ± 0.25 μM) and HeLa cells (IC50 = 17.52 ± 0.09 and 24.14 ± 0.86 μM) and low toxicity against the HFL-1 (IC50 = 114.50 ± 0.01 and 173.20 ± 10 μM). The flow cytometry was further used to confirm the anticancer activity of potent derivatives against the A549 cancer cell line. DNA binding interaction of anticancer agents 3a and 3h with Ct-DNA has been carried out by absorption, fluorescence, EtBr (dye displacement assay), circular dichroism, cyclic voltammetry and time-resolved fluorescence, which showed noncovalent binding mode of interaction. Anticancer activity of both lead compounds (3a and 3h) may be attributed to DNA binding. The evaluation of the antioxidant potential of pyrazoline analogs 3a and 3h by 2,2-diphenyl-1-picrylhydrazyl free radical showed promising antioxidant activity with IC50 values of 0.132 ± 0.012 and 0.215 ± 0.025 μg/mL, respectively. In silico molecular docking of pyrazoline derivatives was also performed using autodock vina software against the DNA hexamer with PDB ID: 1Z3F and ADMET properties to explore their best hits.

QSAR, homology modeling, and docking simulation on SARS-CoV-2 and pseudomonas aeruginosa inhibitors, ADMET, and molecular dynamic simulations to find a possible oral lead candidate

BackgroundIn seek of potent and non-toxic iminoguanidine derivatives formerly assessed as active Pseudomonas aeruginosa inhibitors, a combined mathematical approach of quantitative structure-activity relationship (QSAR), homology modeling, docking simulation, ADMET, and molecular dynamics simulations were executed on iminoguanidine derivatives. ResultsThe QSAR method was employed to statistically analyze the structure-activity relationships (SAR) and had conceded good statistical significance for eminent predictive model; (GA-MLR: Q2LOO = 0.8027; R2 = 0.8735; R2ext = 0.7536). Thorough scrutiny of the predictive models disclosed that the Centered Broto-Moreau autocorrelation - lag 1/weighted by I-state and 3D topological distance-based autocorrelation—lag 9/weighted by I-state oversee the biological activity and rendered much useful information to realize the properties required to develop new potent Pseudomonas aeruginosa inhibitors. The next mathematical model work accomplished here emphasizes finding a potential drug that could aid in curing Pseudomonas aeruginosa and SARS-CoV-2 as the drug targets Pseudomonas aeruginosa. This involves homology modeling of RNA polymerase-binding transcription factor DksA and COVID-19 main protease receptors, docking simulations, and pharmacokinetic screening studies of hits compounds against the receptor to identify potential inhibitors that can serve to regulate the modeled enzymes. The modeled protein exhibits the most favorable regions more than 90% with a minimum disallowed region less than 5% and is simulated under a hydrophilic environment. The docking simulations of all the series to the binding pocket of the built protein model were done to demonstrate their binding style and to recognize critical interacting residues inside the binding site. Their binding constancy for the modeled receptors has been assessed through RMSD, RMSF, and SASA analysis from 1-ns molecular dynamics simulations (MDS) run. ConclusionOur acknowledged drugs could be a proficient cure for SARS-CoV-2 and Pseudomonas aeruginosa drug discovery, having said that extra testing (in vitro and in vivo) is essential to explain their latent as novel drugs and manner of action.