Structure-activity Relationship Studies Research Articles

Chalcones As Broad‐Spectrum Antimicrobial Agents: A Comprehensive Review And Analysis Of Their Antimicrobial Activities

AbstractThe rise of drug‐resistant microbes necessitates the development of new antimicrobial agents. Increasing resistance among multidrug‐resistant microbes has spurred research efforts to overcome drug resistance through novel scaffolds and strategies. Chalcones, distinguished by their chemical structure of 1,3‐diphenylprop‐2‐en‐1‐one, have exhibited a multifaceted array of biological activities, prominently including antimicrobial and antiviral properties. Modifying the structure by adding substituent groups to the aromatic ring enhances potency, reduces toxicity, and expands pharmacological effects. This review highlights the potential of chalcones and analogues in preventing diseases affected by diverse antibiotic resistance genes, including viruses, bacteria, fungal spores, and Plasmodiidae. Our analysis underscores the fact that a multitude of chalcone compounds effectively obstruct various molecular targets pivotal in the development of antibiotic resistance, thus rendering bacteria vulnerable to conventional antibacterial agents and potentially obliterating resistance mechanisms. Certain chalcone compounds exhibit higher activity levels compared to traditional antibiotics like vancomycin and tetracycline. Additionally, Docking and SAR studies of chalcones summarize their role in developing novel drugs. Chalcones and their derivatives demonstrate promising broad‐spectrum antimicrobial activities. Investigating structure‐activity relationships (SAR) enhances our understanding of chalcone‐based drug design, enabling the development of more effective therapeutic interventions against the pressing global health challenge of antimicrobial resistance.

Development of Conformationally Restricted Negamycin Derivatives for Potent Readthrough Activity.

(+)-Negamycin, which is a dipeptide-like antibiotic containing a hydrazide structure, exhibits readthrough activity, resulting in the restoration of dystrophin in the mdx mouse model of Duchenne muscular dystrophy (DMD). In our previous structure-activity relationship study of negamycin, we found that its natural analogue 3-epi-deoxynegamycin (TCP-107), without antimicrobial activity, showed a higher readthrough activity than negamycin. In this study, we designed and synthesized cyclopropane-based conformationally restricted derivatives of TCP-107 and evaluated their readthrough activity in the cell-based reporter assay against a TGA-type mutation derived from DMD. As a result, a down-cis isomer, TCP-304, showed significant readthrough activity among the four isomers. Moreover, TCP-306, a derivative acylated by l-α-aminoundecanoic acid, possessed approximately 3 times higher activity than TCP-304. These down-cis derivatives showed dose-dependent readthrough activity and were effective for not only TGA but also TAG mutations. These results suggest that the conformational restriction of negamycin derivatives by the introduction of the cyclopropane ring is effective for an exhibition of potent readthrough activity.

Prioritizing pharmaceutically active compounds (PhACs) based on occurrence-persistency-mobility-toxicity (OPMT) criteria: an application to the Brazilian scenario

ABSTRACT A study of Quantitative Structure Activity Relationship (QSAR) was performed to assess the possible adverse effects of 25 pharmaceuticals commonly found in the Brazilian water compartments and to establish a ranking of environmental concern. The occurrence (O), the persistence (P), the mobility (M), and the toxicity (T) of these compounds in the Brazilian drinking water reservoirs were evaluated. Moreover, to verify the predicted OPMT dataset outcomes, a quality index (QI) was also developed and applied. The main results showed that: (i) after in silico predictions through VEGA QSAR, 19 from 25 pharmaceuticals consumed in Brazil were classified as persistent; (ii) moreover, after in silico predictions through OPERA QSAR, 15 among those 19 compounds considered persistent, were also classified as mobile or very mobile. On the other hand, the results of toxicity indicate that only 9 pharmaceuticals were classified with the highest toxicity level. Ultimately, the QI of 7 from 25 pharmaceuticals were categorized as ‘optimal’; 15 pharmaceuticals were categorized as ‘good’; and only 3 pharmaceuticals were categorized as ‘regular’. Therefore, based on the QI criteria used, it is possible to assume that this OPMT prediction dataset had a good reliability. Efforts to reduce emissions of OPMT-pharmaceuticals in Brazilian drinking water reservoirs are encouraged.

Low-temperature CeCoMnOx spinel-type catalysts prepared by oxalate co-precipitation for selective catalytic reduction of NO using NH3: A structure–activity relationship study

CeCoMnOx spinel-type catalysts for the selective catalytic reduction of NO using NH3 (NH3-SCR) are usually prepared by alkaline co-precipitation. In this paper, a series of CeCoMnOx spinel-type catalysts with different calcination temperatures were prepared by acidic oxalate co-precipitation. The physicochemical structures and NH3-SCR activities of the CeCoMnOx spinel-type catalysts prepared by oxalate co-precipitation and conventional ammonia co-precipitation were systematically compared. The results show that the CeCoMnOx spinel-type catalysts prepared by the oxalate precipitation method (CeCoMnOx-C) have larger specific surface area, more mesopores and surface active sites, stronger redox properties and adsorption activation properties than those prepared by the traditional ammonia co-precipitation method at 400 °C (CeCoMnOx-N-400), and thus CeCoMnOx-C have better low-temperature NH3-SCR performance. At the same calcination temperature of 400 °C, the NO conversion of CeCoMnOx-C-400 exceeds 89 % and approaches 100 % within the reaction temperature of 100–125 °C, which is 14.8 %-2.5 % higher than that of CeCoMnOx-N-400 at 100–125 °C. In addition, the enhanced redox and acid cycle matching mechanisms on the CeCoMnOx-C surface, as well as the enhanced monoadsorption Eley-Rideal (E-R) and double adsorption Langmuir-Hinshelwood (L-H) reaction mechanisms, are also derived from XPS and in situ DRIFTS characterization.

Abstract C044: Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer

Abstract The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia H1-related phosphatase (VHR) was reported to exhibit elevated protein level in cervix cancer cell lines compared to normal keratinocytes implicating VHR as a novel target for cervical cancer therapeutic. VHR belongs to the superfamily of protein tyrosine phosphatases (PTPs), a large class of human enzymes that is notoriously difficult to target with small molecules. Recent studies have demonstrated some PTP functions as oncogenes to promote tumor development including SHP2 (PTPN11), PTP1B (PTPN1), and VHR (DUSP3). Fragment-based drug discovery (FBDD) has merged as an effective strategy to provide potent ligands, particularly for challenging drug targets such as PTPs. In this study, we present an NMR-based discovery platform designed to discovery fragment hits that exhibit binding affinity to VHR. Our platform employed fluorine NMR, a robust ligand-observed NMR method, to screen fragment library. Subsequent validation of confirmed hits was accomplished through a series of biophysical and biochemical experiments. Structural study such as X-ray crystallography provide binding mode of action of potent molecules with the VHR protein. Using this platform, we have successfully identified several potent fragments that displayed relative selectivity for VHR. Furthermore, We discovered novel ligand binding sites distinguished from the active site. Initial structure-activity relationship (SAR) studies were also conducted, enabling us to explore a set of validated fragment hits that serve as starting point for medicinal chemistry optimization. Moreover, our fragment discovery platform is a promising strategy for discovering potent and selective fragments targeting other PTPs, thereby offering potential therapeutic options for a boarder spectrum of cancer types. Citation Format: Jiaqian WU, Marek R Baranowski, Nicholas D.P. Cosford, Lutz Tautz. Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C044.

In silico-based identification of new anti-pfdhfr drug candidates via 1,3,5-triazine derivatives

Quantitative structure-activity relationship study was used to investigate the relationship between anti-pfdhfr activity and structure of twenty-eight 1,3,5-triazine derivatives. We performed benchmark studies on the molecular geometry, electron properties of 1,3,5-triazine using semi-empirical(PM3), density functional theory and post Hartree-Fock methods. Followed by a QSAR study using multiple linear regression (MLR) and artificial neural networks (ANN). The QSAR models developed allow identify/describe the relationship between the biological activity of the molecules and their molecular descriptors (topological, physicochemical, electronic...). A further external set of compounds was used for validation where a high correlation between experimental and predicted anti-pfdhfr activity values is noticed. This QSAR study provides useful information for developing novel pfdhfr inhibitors. The set’s ADME properties and drug similarities, as well as newly produced compounds and reference ligand, were investigated. These findings would be extremely useful in guiding optimization for the development of new anti-pfdhfr drug candidates.

Abstract A034: Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme

Abstract Introduction. Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor in adults with a survival of only 12-15 months. GBM stem cells contribute to resistance to the DNA-damaging first-line chemotherapy, temozolomide, which accounts for tumor recurrence and treatment failure. Amplification of epidermal growth factor receptor (EGFR) is one of the most common genetic alterations associated with GBM aggressiveness. Despite the evidence that EGFR-induced pathway represents an attractive therapeutic target in GBM, gefitinib, an orally active selective EGFR-tyrosine kinase inhibitor, showed only a limited potency in clinical trials. We previously showed that ZR2002, an aminoquinazoline “combi-molecule” designed to possess mixed EGFR tyrosine kinase inhibition and DNA damaging properties, induced submicromolar cytotoxic activity against GBM stem cells resistant to temozolomide and gefitinib. Significantly increased survival of mice harboring an intracranially implanted aggressive temozolomide-resistant tumour by comparison with the clinical treatment gefitinib. Furthermore, mass spectrometry imaging provided evidence of its ability to cross the blood–brain barrier but metabolites devoid of its critical 2-chloroethyl DNA alkylating function were observed. Given that the loss of DNA alkylating species may decrease efficacy in vivo, here we show a structure-activity relationship study toward structures with increased stability to metabolic dealkylation. Materials and methods. Three glioblastoma cells line (U87-wt, U87-EGFR and U87-EGFRvIII) were used to determine IC50 of the new molecules with SRB assay. CD1 mice were treated with a dose of 100mg/kg by oral gavage and analyzed after 3h. Drug metabolism was measured by LC-MS. Results. In vitro growth inhibitory showed that the new analogues have the same cytotoxicity profile as ZR2002. In vivo analysis in mice administered p.o. with the new analogues showed that our newly synthesized molecules were less metabolized than ZR2002 using the ratio of intact structure levels/over metabolites as a parameter that we defined as extent of metabolism. Furthermore, they were found to maintain good brain penetration. Conclusions. These results proved that we were able to design and synthesize combi-molecules that can escape metabolism and preserve the 2-chloroethyl in vivo, a group that is required for the dual activity of the combi-molecules. Importantly, the combi-molecules, despite the structural change, remain very water soluble and available orally. Citation Format: Ana Belen Fraga-Timiraos, Caterina Facchin, Anne-Laure Larroque-Lombard, Bertrand Jacques Jean-Claude. Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A034.

An insight into the structure-activity relationship studies of anticancer medicinal attributes of 7-azaindole derivatives: a review.

In the current portfolio, there is a lot of interest in the 7-azaindole building block for drug discovery. The creation of synthetic, sophisticated methods for the modification of 7-azaindoles is a promising area of research. This review covers the structure-activity relationship of 7-azaindole analogs, which have been shown to beeffective anticancer agents in the literature of the past twodecades. Positions 1, 3and 5 of the 7-azaindole ring arethe most active sites. Disubstitution is used for the synthesis of a new analog of the 7-azaindole moiety. All positions are used to create novel molecules that areeffective anticancer agents. The alkyl, aryl carboxamide group and heterocyclic ring are the most successful types of substitution.

Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer's Candidates.

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1-17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 1-17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.

Antiviral activity of porphyrins and porphyrin-like compounds against tick-borne encephalitis virus: Blockage of the viral entry/fusion machinery by photosensitization-mediated destruction of the viral envelope

Tick-borne encephalitis virus (TBEV), the causative agent of tick-borne encephalitis (TBE), is a medically important flavivirus endemic to the European–Asian continent. Although more than 12,000 clinical cases are reported annually worldwide, there is no anti-TBEV therapy available to treat patients with TBE. Porphyrins are macrocyclic molecules consisting of a planar tetrapyrrolic ring that can coordinate a metal cation. In this study, we investigated the cytotoxicity and anti-TBEV activity of a large series of alkyl- or (het)aryl-substituted porphyrins, metalloporphyrins, and chlorins and characterized their molecular interactions with the viral envelope in detail. Our structure–activity relationship study showed that the tetrapyrrole ring is an essential structural element for anti-TBEV activity, but that the presence of different structurally distinct side chains with different lengths, charges, and rigidity or metal cation coordination can significantly alter the antiviral potency of porphyrin scaffolds. Porphyrins were demonstrated to interact with the TBEV lipid membrane and envelope protein E, disrupt the TBEV envelope and inhibit the TBEV entry/fusion machinery. The crucial mechanism of the anti-TBEV activity of porphyrins is based on photosensitization and the formation of highly reactive singlet oxygen. In addition to blocking viral entry and fusion, porphyrins were also observed to interact with RNA oligonucleotides derived from TBEV genomic RNA, indicating that these compounds could target multiple viral/cellular structures. Furthermore, immunization of mice with porphyrin-inactivated TBEV resulted in the formation of TBEV-neutralizing antibodies and protected the mice from TBEV infection. Porphyrins can thus be used to inactivate TBEV while retaining the immunogenic properties of the virus and could be useful for producing new inactivated TBEV vaccines.

Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia

Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.

Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.

As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic cancer and several potentially useful tool compounds.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure–activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure–activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.

A New Class of Synthetic Type-B Polycyclic Polyprenylated Acylphloroglucinols (PPAP-B) Overcomes Venetoclax-Resistance in Acute Myeloid Leukemia (AML)

Venetoclax (VEN) resistance in AML therapy is a field of unmet need. VEN selectively binds in the BH3-binding groove of BCL-2 to release BIM leading to pore-forming BAX/BAK dimerization to finally release cytochrome C, as the “step of no return” in induction of programmed cell death. Compensatory overexpression of other BCL-2 family members such as MCL-1 and BCL-XL is a well described resistance mechanism to restore the ability to sequester BIM and therefore compensate for BCL-2 inhibition. Type-B PPAP are a novel class of neoplastic therapeutics. A new synthetic toolbox for the coupling of a bioactive head group (R 3) enabled the generation of novel, highly active PPAPs, which are low-toxic, water-soluble and photochemically stable - and therefore attractive compounds for clinical development. We now provide evidence that PPAP-B possess antileukemic activity in in vitro and ex vivo AML models via induction of the mitochondrial apoptosis pathways. Further, PPAP-B suppress transcription of MCL-1 and BCL-XL - leading to highly synergistic induction of apoptosis in combination with venetoclax, including a Venetoclax-resistant AML model. Employing structure-activity relationship (SAR) studies, newly generated PPAPs (#22-#144) were tested in acute leukemia HL60, Molm14 and OCI-AML-3 cell lines as well as freshly harvested native leukemia blasts from consented patients. Physiologic mononuclear cells (MC) extracted from cord blood or healthy donors were used as controls. PPAPs were modified step-by-step regarding their chemical structure and assessed in dose dilution series to determine antileukemic efficacy of the compounds. The capability to induce apoptosis and inhibit proliferation was assessed, using standard techniques. To shed light on the underlying mechanism of action, Proteome Profiler Arrays (R&D systems) were performed and confocal microscopy was employed to trace specific fluorescent PPAPs within the cell. Together, the SAR approach led to improvement of IC50 rates of PPAP-B ranging from 20 μM to now < 4 μM. Compound #122 was thereby identified as the most potent PPAP with respect to inhibition of proliferation and induction of apoptosis. Genotoxic studies, as evidenced in a thymidine kinase mouse lymphoma assay (MLA), did not point to potential genotoxicity. Confocal microscopy confirmed accumulation of PPAPs in the cytosol and outer mitochondrial layer using fluorescent PPAPs. In line, induction of mitochondrial apoptosis was seen as evidenced by BAX activation, release of cytochrome C and cleavage of caspases 8 and 3. Further, PPAP-B suppressed transcription of MCL-1 and BCL-XL, putatively via inhibition of the JAK-STAT pathway as discussed earlier. These observations suggest a role of PPAPs in overcoming VEN-resistance in AML. Indeed, combination of PPAP #122 with VEN was highly synergistic with regard to induction of apoptosis, already at doses where the single agents did not display pro-apoptotic activity (e.g. PPAP #122 2.5 μM: 10%, VEN 5nM: 5%, PPAP/VEN combination:74% apoptotis). Most interestingly, PPAP #122 displayed strong pro-apoptotic activity in VEN-resistant leukemia models (MOLM14, HL60, OCi-3 models) with a IC50s < 1μM, and in combination with VEN, re-sensitized cells towards Venetoclax in a combination approach. Together, further development of type-B PPAPs to target Venetoclax resistance in AML is a promising approach to overcome a so far unmet clinical need in acute leukemias.

Investigating Graph Invariants for Predicting Properties of Chemical Structures of Antiviral Drugs

In the study of the Quantitative Structure-Activity Relationship (QSAR) model, the topological index of a molecular structure as a molecular descriptor is used to analyze their molecular characteristics. Theoretical evaluation of the drug’s molecular structure helps to accelerate the process of design and discovery of drugs by understanding its mechanism of action. In this paper, we study the molecular structure of antiviral drugs, namely, Ritonavir and Lopinavir using the graph theory and the edge-partition approach. We determine the exact formula of some new Sombor-type topological indices and Sombor-type topological coindices of the molecular graph and line graph of the chemical structures of the antiviral drugs Ritonavir and Lopinavir. In this study, we apply Matlab and Mathematica software to evaluate the results and accuracy of calculations. The linear regression approach in the quantitative structure-property relationships model is used to investigate the relationships between Sombor indices and coindices and physicochemical properties.

Lead to hit ruthenium-cyclopentadienyl anticancer compounds: Cytotoxicity against breast cancer cells, metabolic stability and metabolite profiling

The successful choice of hit compounds during drug development programs involves the integration of structure-activity relationship (SAR) studies with pharmacokinetic determinations, including metabolic stability assays and metabolite profiling.A panel of nine ruthenium-cyclopentadienyl (RuCp) compounds with the general formula [Ru(η5-C5H4R)(PPh3)(bipyR')]+ (with R = H, CHO, CH2OH; R' = H, CH3, CH2OH, CH2Biotin) has been tested against hormone-dependent MCF-7 and triple negative MDA-MB-231 breast cancer cells. In general, all compounds showed important cytotoxicity against both cancer cell lines and were able to inhibit the formation of MDA-MB-231 colonies in a dose-dependent manner, while showing selectivity for cancer cells over normal fibroblasts. Among them, four compounds stood out as lead structures to be further studied. Cell distribution assays revealed their preference for the accumulation at cell membrane (Ru quantification by ICP-MS) and the mechanism of cell death seemed to be mediated by apoptosis. Potential structural liabilities of lead compounds were subsequently flagged upon in vitro metabolic stability assays and metabolite profiling. The implementation of this integrated strategy led to the selection of RT151 as a promising hit compound.

Synthesis, structure–activity relationship studies using density functional theory and in silico molecular docking on substituted benzohydrazide derivatives

The present study demonstrates the utility of benzohydrazide derivatives based on an approach to identify potential targets for a series of synthesized compounds that show potent anticancer activities against four cancer cell lines compared to other structurally related molecules. Benzohydrazide compounds have been synthesized effectively by the condensation of aldehyde and hydrazide at a 1:1 molar ratio. The complete series of compounds 1a-j were characterized by FT-IR, NMR, and one of them by single-crystal X-ray diffraction. The crystal structure of compound 1a shows a trans configuration around the CN bond and crystallized in a monoclinic system with C 2/c space group. All compounds exhibited good anticancer activity against four cancer cell lines such as A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HT-29 (human epithelial intestinal) and MDA-MB-232(human metastatic breast). Among them, compound 1e shows the highest cytotoxic effect against the HT29 (IC50 = 0.47 µM) and A375 (IC50 = 0.80 µM) cell lines. Other compounds also exhibited promising anticancer activity. In addition, the nontoxic action was verified using the cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human red blood cells. Parameters such as HOMO-LUMO energies, Hirshfeld surface analysis, and Molecular Electrostatic Potential (MEP) surface have been calculated using DFT and compared to experimental values of compounds 1a-c. In silico molecular docking studies revealed that the compound 1 h interacted very strongly with the 1T46 protein, with a docking score of −9.7 kcal/mol and very good binding via π–π, π-alkyl and π–σ interactions as compared to the standard drug. As a result of their potent cytotoxicity activities and computational analysis, these can be considered promising anticancer agents.

One-step microwave enhanced synthesis, biological evaluation, and molecular modeling investigations of donepezil analogs as acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) is an important enzyme that hydrolyzes the neurotransmitter acetylcholine. Inhibiting AChE represents one of the therapeutic strategies for treating the symptoms of Alzheimer’s disease (AD). To date, only several AD drugs have been approved by the U.S. Food and Drug Administration, with donepezil being the most commonly used. In this study, we synthesized 46 donepezil-based analogs via a one-step microwave-assisted synthetic route and evaluated them in vitro using an AChE inhibition assay in order to better understand structural requirements important for the inhibition. Our structure–activity relationship studies revealed that various halogens, electron-withdrawing, and electron-donating groups placed in the ortho- and meta-positions on the phenyl moiety of donepezil are generally well-tolerated, yielding potent AChE inhibitors in the low nanomolar range similar to donepezil, while polysubstitutions led to moderate or significant decreases in inhibition potency.

Density Functional Theory-Guided Photo-Triggered Anticancer Activity of Curcumin-Based Zinc(II) Complexes.

Photodynamic therapy (PDT) has evolved as a new therapeutic modality for cancer treatment with fewer side effects and drug resistance. Curcumin exhibits PDT activity, but its low bioavailability restricts its clinical application. Here, the bioavailability of curcumin was increased by its complex formation with the Zn(II) center. For a structure-activity relationship study, Zn(II)-based complexes (1-3) comprising N^N-based ligands (2,2'-bipyridine in 1 and 2 or 1,10-phenanthroline in 3) and O^O-based ligands (acetylacetone in 1, monoanionic curcumin in 2 and 3) were synthesized and thoroughly characterized. The X-ray structure of the control complex, 1, indicated a square pyramidal shape of the molecules. Photophysical and TD-DFT studies indicated the potential of 2 and 3 as good visible light type-II photosensitizers for PDT. Guided by the TD-DFT studies, the low-energy visible light-triggered singlet oxygen (1O2) generation efficacy of 2 and 3 was explored in solution and in cancer cells. As predicted by the TD-DFT calculations, these complexes produced 1O2 efficiently in the cytosol of MCF-7 cancer cells and ultimately displayed excellent apoptotic anticancer activity in the presence of light. Moreover, the molecular docking investigation showed that complexes 2 and 3 have very good binding affinities with caspase-9 and p-53 proteins and could activate them for cellular apoptosis. Further molecular dynamics simulations confirmed the stability of 3 in the caspase-9 protein binding site.

Highlights on quinolonic compounds with changes on the basic structure as promising molecules to new drugs

The introduction of quinolonic antimicrobials on the market caused a revolution in antibacterial therapy. 4-quinolone skeleton became the target of many studies of structure-activity relationship establishing the parameters considered optimal for the development of new quinolonic antibiotics. These parameters limited the development of new compounds, so it is possible finding compounds with changes in the same position with similar substituents. The purpose of this article is to identify quinolonic compounds which do not fit into one or more criteria determined as ideal in the structure-activity relationship studies for quinolonic antibiotics and exemplify that it is possible to develop of even more active compounds making changes in previously unalterable positions.