Drug-like Properties Research Articles

Discovery of New 3-(Benzo[b]Thiophen-2-yl)Pyrrolidine-2,5-Dione Derivatives as Potent Antiseizure and Antinociceptive Agents—In Vitro and In Vivo Evaluation

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED50 (MES) = 27.4 mg/kg and ED50 (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD50 > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain.

Abstract PR004: Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies

Abstract Purpose and rational for the study: The purpose of the study was to develop novel 2nd generation ribosomal RNA synthesis inhibitors for cancer treatment. Ribosome biogenesis (RiBi) is essential for cell growth and proliferation. Transcription of ribosomal RNA genes by Pol I is a critical step in RiBi and is tightly regulated by tumor suppressors and oncoproteins. Indeed, the ability of the potent oncoprotein, MYC, to drive RiBi is necessary for its oncogenic activity (Bywater et al., Cancer Cell, 2011). These data suggested that targeting RiBi, might be a promising strategy to treat malignancies, especially those driven by MYC. To test this, we developed the 1st small molecule inhibitor of Pol I transcription, CX-5461 (Drgyin et al., Cancer Research 2011). While CX-5461 has shown promising activity in pre-clinical studies (Bywater et al., Cancer Cell, 2011; Rebello et al., Clin Cancer Res., 2016; Hein et al., Blood, 2017) and in early Phase trials (Khot et al., Cancer Discovery, 2019; Hilton et al., Nat Commun. 2022) its mechanism of action remains controversial with evidence of off-target activity inducing DNA damage through inhibition of TOPO2a (Cameron et al., Biomedicines, 2024; Koh et al., Nature Genetics, 2024). Thus, to determine if selective inhibition of Pol I transcription in the absence of DNA damage can be used to therapeutical treat cancer in vivo, we developed a series of more selective 2nd generation Pol I inhibitors with our lead compound being PMR-116. Methods and summary of data: We demonstrate that PMR-116 is selective for inhibition of Pol I over Poll II transcription and functions by stalling the Pol I complex at the rDNA promoter. PMR-116, exhibits improved drug-like properties and pharmacokinetics compared to 1st generation CX-5461. As a single agent PMR-116 efficiently treats a range of pre-clinical models of hematologic and solid tumors including lymphoma, AML, hepatocellular carcinoma and prostate cancer. MYC expression positively correlates with sensitivity to PMR-116 in human cancer cell lines and high MYC tumors in vivo are exceptionally sensitive to PMR-116. In contrast to CX-5461, the therapeutic response to PMR-116 occurs in the absence of DNA damage suggesting that DNA damage is not an obligatory response to Pol I transcription inhibition but rather an off-target effect of the 1st generation drug. Small molecule drug combination screens in AML cells demonstrate that PMR-116 works synergistically to reduce cell viability with a range of drugs including carfilzomib and quisinostat used for treatment of hematologic malignancies. Conclusions: Our data establishes inhibition of RNA polymerase I as a bone fide therapeutic target for cancer therapy and demonstrated that PMR-116 is a promising new broad- spectrum anti-cancer drug particularly for those tumors driven by MYC, which are highly refractory to standard therapies. Based on these data we have launched a Phase I clinical trial of PMR-116 in patients with advanced solid tumors (CTRN12620001146987). Citation Format: Rita Ferreira, Katherine M. Hannan, Konstantin Panov, Thejanni Udumanne, Amee J George, Zaka Yuen, Perlita Poh, Eric Kusnadi, Alisee Huglo, Mitchell Lawrence, Mustapha Haddach, Denis Drygin, Luc Furic, Ross D Hannan, Nadine Hein. Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR004.

Riddelline from Tamarix articulate as a potential anti-bacterial lead compound for novel antibiotics discovery: A comprehensive computational and toxicological studies.

Tamarix articulate from the Tamaricaece family is a halophytic plant. This plant is commonly called Athal or Tamarix in different Arabic and Asian countries. Due to the high load of polyphenolic phytochemicals, the plant has been used as a therapeutic option against several diseases for decades. The plant is an anti-inflammatory, anti-bacterial, anti-viral, anti-cancer, anti-oxidant, and anti-inflammatory. In this work, the 222 phytochemical compounds of T. articulate from our previous study are used in different bioinformatic and biophysics techniques to explore their biological potency against different anti-bacterial, anti-cancer and anti-viral targets. By doing so, it was found that Riddelline ranked as the best binding molecule of biological macromolecules selected herein in particular the bacterial targets. The binding energy value of the compound for the KdsA enzyme was -14.64 kcal/mol, KdsB (-13.09 kcal/mol), MurC (-13.67 kcal/mol), MurD (-13.54 kcal/mol), MurF (-14.20 kcal/mol), Polo-like kinase 1 (Plk1) (-12.34 kcal/mol), Bcl-2 protein (-13.39 kcal/mol), SARS-CoV-2 main protease enzyme (-12.67 kcal/mol), and Human T cell leukemia virus protease (-13.67 kcal/mol). The mean Rg value of KdsA-Riddelline complex and KdsA-FPE complex is 32.67 Å, and average RMSD of KdsA-Riddelline complex and KdsA-FPE complex is 2.31 Å, respectively. The binding energy complexes was found to be dominated by van der Waals (-71.98 kcal/mol for KdsA-Riddelline complex and -65.09 kcal/mol for KdsA-FPE complex). The lead compound was also unveiled to show favorable druglike properties and pharmacokinetics. Together, the data suggest the good anti-bacterial activities of the T. articulate phytochemicals and thus can be subjected to experimental in vitro and in vivo investigations.

AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors.

Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with the angiotensin-converting enzyme II (ACE2) receptor of the host cells. Therefore, pharmacological targeting of this interaction might prevent infection or spread of the virus. Here, we performed a virtual screening to identify small molecules that block S-ACE2 interaction. Large compound libraries were filtered for drug-like properties, promiscuity and protein-protein interaction-targeting ability based on their ADME-Tox descriptors and also to exclude pan-assay interfering compounds. A properly designed AI-based virtual screening pipeline was applied to the remaining compounds, comprising approximately 10% of the starting data sets, searching for molecules that could bind to the RBD of the S protein. All molecules were sorted according to their screening score, grouped based on their structure and postfiltered for possible interaction patterns with the ACE2 receptor, yielding 31 hits. These hit molecules were further tested for their inhibitory effect on Spike RBD/ACE2 (19-615) interaction. Six compounds inhibited the S-ACE2 interaction in a dose-dependent manner while two of them also prevented infection of human cells from a pseudotyped virus whose entry is mediated by the S protein of SARS-CoV-2. Of the two compounds, the benzimidazole derivative CKP-22 protected Vero E6 cells from infection with SARS-CoV-2, as well. Subsequent, hit-to-lead optimization of CKP-22 was effected through the synthesis of 29 new derivatives of which compound CKP-25 suppressed the Spike RBD/ACE2 (19-615) interaction, reduced the cytopathic effect of SARS-CoV-2 in Vero E6 cells (IC50 = 3.5 μM) and reduced the viral load in cell culture supernatants. Early in vitro ADME-Tox studies showed that CKP-25 does not possess biodegradation or liver metabolism issues, while isozyme-specific CYP450 experiments revealed that CKP-25 was a weak inhibitor of the CYP450 system. Moreover, CKP-25 does not elicit mutagenic effect on Escherichia coli WP2 uvrA strain. Thus, CKP-25 is considered a lead compound against COVID-19 infection.

Gen-AI Methods, Molecular Docking and Molecular Dynamics Simulations for Identification of Novel Inhibitors of MmPL3 Transporter of Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), the bacterium responsible for tuberculosis (TB), employs mycolic acids to build its cell wall. This robust structure plays a vital role in protecting the bacterium from external threats and contributes to its resistance against antibiotics. Mycobacterial membrane protein Large 3 (MmpL3), a secondary resistance nodulation division transporter, is essential in mycolic acid biosynthesis, transporting mycolic acid precursors into the periplasm using the proton motive force. Due to its role in bacterial cell wall formation, it is a promising target for new tuberculosis treatments. In this study, starting with 85 known MmPL3 compounds, the artificial intelligence (AI)-assisted tool “Design of Druglike Analogues (DeLA-Drug)” was employed to generate about 15,000 novel molecules. These compounds were then subjected to structure-based high-throughput virtual screening and molecular dynamics (MD) simulations to identify potential novel inhibitors of MmpL3. The binding affinity was obtained by docking the above molecules at the SQ109 binding site in MmPL3, followed by pharmacokinetics and toxicity, which were used to reduce the chemical space. Finally, five ligands were subjected to 100 ns MD simulations to investigate the binding energetics of inhibitors to MmpL3. These compounds demonstrated stable binding and favorable drug-like properties, indicating that they could serve as potential novel inhibitors of MmpL3 for Mtb.

Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery.

Peptides can operate as therapeutic agents that sit within a privileged space between small molecules and larger biologics. Despite examples of their potential to regulate receptors and modulate disease pathways, the development of peptides with drug-like properties remains a challenge. In the quest to optimize physicochemical parameters and improve target selectivity, unnatural amino acids (UAAs) have emerged as critical tools in peptide- and peptidomimetic-based drugs. The utility of UAAs is illustrated by clinically approved drugs such as methyldopa, baclofen, and gabapentin in addition to small drug molecules, for example, bortezomib and sitagliptin. In this Perspective, we outline the strategy and deployment of UAAs in FDA-approved drugs and their targets. We further describe the modulation of the physicochemical properties in peptides using UAAs. Finally, we elucidate how these improved pharmacological parameters and the role played by UAAs impact the progress of analogs in preclinical stages with an emphasis on the role played by UAAs.

DDDR-15. UTILIZING DEEP DOCKING AND ARTIFICIAL INTELLIGENCE FOR THE DISCOVERY OF NOVEL PARP1-SELECTIVE INHIBITORS FOR USE AGAINST BRAIN TUMORS

Abstract Brain tumors, including primary brain tumors and central nervous system (CNS) metastases, remain among the most challenging malignancies to treat, with therapeutic options often limited by the inability of drugs to penetrate the blood-brain barrier. Poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair, and inhibition of PARP1 specifically drives synthetic lethality in BRCA-mutated disease. While they’ve achieved commercial success, first generation PARP inhibitors are limited in their utility as they cannot readily pass through the blood-brain barrier and have adverse side effects, likely driven by the collateral inhibition of PARP2. Development of a PARP1-selective, CNS penetrant inhibitor could reduce toxicity, while providing a new therapeutic option for brain tumors. Traditional drug discovery methods are time-consuming and costly, necessitating innovative approaches. Here, we describe the application of Deep Docking, an advanced artificial intelligence (AI) approach, to discover a novel, PARP1-selective inhibitor for use against brain tumors. Deep Docking utilizes deep learning to accelerate the prediction of the binding affinity of a large number of compounds to target proteins, streamlining the virtual screening process and allowing for rapid docking of billions of compounds against the PARP1 protein. Additionally, state-of-the-art generative algorithms and deep learning techniques for predicting drug-like properties such as metabolism, permeability, and safety profiles, can be combined to rapidly perform hit-to-lead optimization. We will present preliminary Deep Docking screening results from billions of compounds, identifying several with predicted high binding affinities for PARP-1. Validating in vitro and in vivo data, including PARP1 selectivity, metabolic stability, pharmacokinetic profile, CNS penetration and safety profile, will be described. Application of the Deep Docking AI platform is being used to significantly accelerate the discovery of a selective PARP-1 inhibitor for brain tumors. This approach will not only improve the efficiency of drug discovery but also enhance the specificity and efficacy of potential therapeutics.

Exploring the therapeutic potential of marine actinomycetes: a systems biology-based approach for Alzheimer’s disease treatment

Abstract Background This study addresses the urgent need for novel Alzheimer’s Disease (AD) treatments, focusing on the therapeutic potential of marine Actinomycetes compounds. Current AD therapies provide only symptomatic relief, necessitating a paradigm shift toward more effective interventions. Methodology Ninety-one bioactive compounds were methodically identified from Actinomycetes strains in the Indian Ocean. Rigorous ADME analysis and in silico toxicological screening narrowed the selection to 19 compounds, including Helquinoline, Bonactin, Azamerone, and Arcyriaflavin A. These compounds demonstrated favorable drug-like properties and activity against crucial AD targets. Utilizing network pharmacology, a bioactive-target-disease association network was constructed to unveil intricate relationships between compounds and target proteins in the context of AD. Topological analysis highlighted influential targets such as SRC, MAPK1, EGFR, PRKCA, PRKCD, and CDK2. Protein–Protein Interaction (PPI) mapping revealed interconnected pathways influenced by these compounds. Results Focus narrowed to the top 10 pathways associated with key hub–bottleneck genes. The GnRH signaling, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways exhibited remarkable fold enrichment, emphasizing their central roles in AD pathogenesis. The GnRH signaling pathway aligned with endocrine dysregulation in AD, EGFR’s dual role in prion-like propagation and amyloid-β pathology, and ErbB signaling’s multifaceted contributions. Conclusion In conclusion, this study presents marine Actinomycetes compounds as potential poly-pharmacological modulators in AD. Despite promising results, cautious optimism is warranted, requiring further experimental validation. The identified compounds and pathways offer a novel perspective, laying the groundwork for targeted interventions within the intricate landscape of AD. This research contributes to advancing AD therapeutics within a systems biology framework, introducing innovative approaches to address this complex neurodegenerative disorder.

Harnessing curcumin and nanotechnology for enhanced treatment of breast cancer bone metastasis.

Breast cancer (BC) bone metastasis poses a significant clinical challenge due to its impact on patient prognosis and quality of life. Curcumin (CUR), a natural polyphenol compound found in turmeric, has shown potential in cancer therapy due to its anti-inflammatory, antioxidant, and anticancer properties. However, its metabolic instability and hydrophobicity have hindered its clinical applications, leading to a short plasma half-life, poor absorption, and low bioavailability. To enhance the drug-like properties of CUR, nanotechnology-based delivery strategies have been employed, utilizing polymeric, lipidic, and inorganic nanoparticles (NPs). These approaches have effectively overcome CUR's inherent limitations by enhancing its stability and cellular bioavailability both in vitro and in vivo. Moreover, targeting molecules with high selectivity towards bone metastasized breast cancer cells can be used for site specific delivery of curcumin. Alendronate (ALN), a bone-seeking bisphosphonate, is one such moiety with high selectivity towards bone and thus can be effectively used for targeted delivery of curcumin loaded nanocarriers. This review will detail the process of bone metastasis in BC, elucidate the mechanism of action of CUR, and assess the efficacy of nanotechnology-based strategies for CUR delivery. Specifically, it will focus on how these strategies enhance CUR's stability and improve targeted delivery approaches in the treatment of BC bone metastasis.

Design And Synthesis Of Novel Thiazole Linked Tetrahydropyridine Analogues As Anticancer Agents.

A library of new thiazole linked tetrahydropyridines (6a-q) synthesized and screened for their invitro anticancer activity against human breast adeno carcinoma cell viz. MCF-7 and MDA-MB-231. The two compounds 6d containing -F and -Cl functions in para and meta position of phenyl ring (9.94 ± 1.02µM, 9.78 ± 1.08µM) and 6e with -Cl and -NH2 functions on pyridine ring (9.72 ± 0.91 µM,9.54 ± 0.95µM) demonstrated outstanding activity against both the cell lines when compared to Doxorubicin. The benzofuran analogue 6o presented good activity with an IC50 value of 12.19 ± 1.03µM (MCF-7) and 12.22 ± 1.07µM (MDA-MB-231). The molecular docking study of potent molecule 6e against crystal structure of breast tumor kinase presented promising docking score and binding interactions. Predicted pharmacokinetics properties of compounds 6a-q and presented boiled diagram of compounds 6d and 6e implied favourable drug-likeness properties.

Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy.

Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure-activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound 13. Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.

Unlocking Neuraminidase Inhibitors: Insights from Natural Products through Pharmacophore Modeling, Virtual Screening, and Molecular Docking

Background: Neuraminidase enzyme plays a major role in the life cycle of influenza viruses. Targeting neuraminidases is a key strategy in preventing and treating influenza A and B spread by inhibiting the release of new viral particles from infected cells. Developing new neuraminidase inhibitors with enhanced efficacy and reduced risk of resistance is the ultimate of ongoing research. Objective: In this study, we tried to shed light on molecules of natural origin that inhibit neuraminidase enzyme by utilizing different aspects of in silico studies. Methods: The work started by generating structure-based pharmacophore, later used for the virtual screening of electronic libraries constructed from chemical and natural compounds. Hits raised from virtual screening were subjected to molecular docking to assess and explain different modes of interactions with the neuraminidase enzyme. Drug likeness and ADME filters were applied to choose compounds that may be taken effectively by oral route with good gastrointestinal absorption and acceptable pharmacokinetics with respect to Lipinski and Ghose rules. The hits were also inspected for toxicity risks, including mutagenic, tumorigenic, irritant, and reproductive effects. Results: 7 features of the generated pharmacophore from the potent inhibitor Oselatamiver were the base for virtual screening. The results obtained by database screening highlighted 4 natural compounds listed in the COCONUT library (CNP 0125691 (Penicitrinol K), CNP0256196 (Frenolicin D), CNP 0138184, and CNP 0206296) as potential neuraminidase inhibitors. The compounds showed a similar interaction profile to Oseltamivir by molecular docking with high binding affinity. The key residue TYR 406 hydrogen bonded to Penicitrinol and Frenolicin D as well as to Oseltamevir. The 4 natural compounds exerted drug-like properties and promising pharmacokinetic characters. Toxicity risks estimations put Penicitrinol K and Frenolicin as devoted to mutagenic, tumorigenic, irritant and reproductive potentials. Penicitrinol K and Frenolicin are assigned for further in vitro and in vivo studies as promising neuraminidase inhibitors. Conclusion: Penicitrinol K, and Frenolicin D are promising natural neuraminidase inhibitors, exhibiting favourable drug-like properties and low toxicity risks in addition to showing the pattern of interaction profiles with neuraminidase enzymes similar to the known drug Oseltamivir contributing to the development of effective antiviral therapies against influenza, suggesting further in vitro and in vivo evaluation.

Research on the pharmacological potential of 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide

The heterocyclic system of 1,2,4-triazole and its derivatives is one of the leaders in the development of highly promising biologically active compounds. The peculiarities of the chemical structure of the derivatives of this heterocycle provide a wide range of possibilities for chemical transformations that allow to obtain really effective drugs. The involvement of several substituents in chemical transformations simultaneously, which have the properties of highly reactive centers, additionally creates favorable conditions for the formation of rational ways to create a biologically active compound. Amino-, mercapto- or hydroxogroups often play the role of such groups in chemistry. The use of these groups as substituents of 1,2,4-triazole synthon provides multifaceted opportunities for directed chemical transformation. The ability of such structural fragments to form chemical interactions and bonds with biological targets has an additional positive effect in the sense of their involvement in chemical transformations on the way to the targeted production of a biologically active substance. Thus, the combination of a heterocyclic structure with a highly reactive chemical center is endowed with theoretically sound and practically significant meaning. The aim of the work is to preliminary determine the potential for creating a biologically active substance with antifungal action based on 1-alkyl derivatives of 3,5-dimethy-l-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide. Materials and methods. The toxicity of the studied compounds has been predicted using the TEST program (Toxicity Estimation Software Tool), which allowed to determine the predictive level of acute toxicity, ecotoxicity and mutagenicity. The physicochemical and pharmacokinetic parameters have been predicted, and the drug-like properties and availability of the investigated substances have been assessed using the online resource SwissADME. The determination of the most favorable spatial configuration of the ligand relative to the active site of the protein and the assessment of the strength of their interaction have been realized using the computational method of molecular docking. The ligands have been prepared using MarvinSketch 6.3.0, HyperChem 8 and AutoDock Tools-1.5.6 software. The preparation of the model enzyme has been based on the use of Discovery Studio 4.0 and AutoDock Tools-1.5.6. The practical implementation of flexible molecular docking has been carried out using the software tools of the AutoDock/Vina platform. Results. In the process of step-by-step prescreening of the formed structures of a number of 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide, a number of qualitative and quantitative indicators related to the physicochemical characteristics and pharmacokinetic parameters of the studied substances have been obtained. According to the results of the first stage of research, the group of substances under consideration can be predictively considered low-toxic, but with a high risk of mutagenic properties. The next stage of the work, which involved the analysis of physicochemical parameters, pharmacokinetic parameters, general drug-like properties and bioavailability, allowed us to identify 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide as substances with a rather positive pharmacological profile. The final stage in the form of molecular docking of the structure of the studied compounds to the active site of lanosterol 14α-demethylase allowed us to determine the nature of the chemical interaction and the type of amino acid residues that may be involved in the antifungal properties of the key ligands. The analysis of the docking results allows us to determine the privileged nature of the nonyl substituent at the first Nitrogen atom of the 1,2,4-triazole synthon in the structure of the presented series of compounds for the formation of antifungal properties. Conclusions. The general prospects for the creation of a biologically active substance with antifungal properties using 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide look quite realistic. Particular attention should be paid to 3,5-dimethyl-1-nonyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide as a substance with significant potential for antifungal properties, which allows us to recommend this compound for further more constructive and extended in vitro and in vivo studies.

Design, synthesis, biological evaluation, and molecular modeling studies of some quinazolin-4(3H)-one-benzenesulfonamide hybrids as potential α-glucosidase inhibitors

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, posing serious health risks and becoming increasingly prevalent. Prolonged hyperglycemia can lead to complications such as nephropathy, neuropathy, retinopathy, cardiovascular damage, and blindness. Controlling hyperglycemia through α-glucosidase inhibitors, which slow down carbohydrate breakdown, is an effective treatment strategy. However, current inhibitors like acarbose, voglibose, and miglitol while used to manage type 2 diabetes, have significant side effects. Therefore, developing new α-glucosidase inhibitors that are more effective and have fewer side effects is crucial. In this study, a series of novel quinazolin-4(3H)-one-benzenesulfonamide hybrid compounds were designed, synthesized, and evaluated for in vitro α-glucosidase inhibitory activity. The compounds showed higher enzyme inhibition potency, with IC50 values ranging between 129.2 ± 0.5 and 558.7 ± 13.7 µM, compared to acarbose (IC50=814.3 ± 13.5 µM). Among the tested compounds, compound 10, bearing a 4-chlorophenyl ring on the nitrogen atom of the sulfonamide group, was the most active, with an IC50 value of 129.2 ± 0.5 µM. Enzyme kinetics analyses and molecular modeling studies were conducted to understand their inhibition mechanisms and interactions with the enzyme. The kinetic studies revealed a mixed-type inhibition model, indicating that the compounds bind to the enzyme-substrate complex with higher affinity than to the free enzyme. Molecular modeling results confirmed these findings. Additionally, in silico prediction studies showed that the selected compounds have favourable physicochemical and drug-like properties. These results suggest these compounds have potential for further optimization and development as effective α-glucosidase inhibitors for diabetes treatment.

In silico prediction of the pharmacological potential of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine

The development of new drug-like molecules based on 7-R-8-hydrazine derivatives of 1,3-dimethylxanthine is promising in view of the known pharmacological effect of theophylline and functional hydrazine derivatives. In silico methods make it possible to rationalize the synthesis and reduce the number of chemical compounds at the stage of virtual screening by eliminating potentially ineffective molecules. The aim of the work was to carry out а virtual design and predictive evaluation of pharmacological activity of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine by in silico methods. Materials and methods. To perform in silico prediction of the pharmacological potential of several new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine, we used the online services. As 12 model compounds, we chose 12 derivatives of 5-(2-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazine)-5-phenylpentanoic acid with linear and branched alkyl substituents at the 7th position of the basic heterocycle: methyl-, ethyl-, n-propyl-, n-butyl, i-butyl, n-amyl, i-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl. The use of the freely available web tool SwissADME made it possible to calculate physicochemical parameters and to determine the drug-likeness properties of molecules. And other Internet platforms allowed to predict the spectrum of biological activity of the target compounds. Results. In silico analysis of the pharmacological potential of model compounds was performed. Three biological actions (peripheral vasodilator, kidney function stimulant, lipoprotein lipase inhibitor) with high Pa values are predicted for all derivatives of the series. The ADME parameters of the molecules were evaluated and their potential drug-like properties were determined. Conclusions. It was established that the extension of the alkyl substituent at the 7th position of the basic heterocycle should lead to a deterioration of the ADME parameters of the molecules, potentially reduce their oral bioavailability, but should not radically affect their biological activity profile. Compounds 1–3 and 5 are predicted to be orally bioavailable. They should be characterized by a wide spectrum of biological activity with the highest probability of vasodilator effect on peripheral vessels. In the future, it is advisable to carry out targeted synthesis of hit compounds and thorough in vitro, in vivo studies, and for compounds with violated physicochemical criteria – structural optimization of molecules in order to find a lead compound.

Molecular docking, ADME properties and synthesis of thiophene sulfonamide derivatives

This study investigates the drug-like properties of target molecules containing thiophene sulfonamide groups (7a–7s) using computational molecular docking techniques. The binding interactions of these derivatives were assessed using protein 2NSD (Enoyl acyl carrier protein reductase InhA, complexed with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB DOI: 10.2210/pdb2NSD/pdb) as the receptor. Molecular docking results revealed notable docking scores for all compounds, ranging from −6 to −12 kcal/mol. Compounds 7e, 7i, and 7f, in particular, demonstrated impressive glide scores (>11 kcal/mol) and were selected for further analysis through molecular dynamics simulations, which provided deeper insights into their dynamic behavior and stability. The drug-like properties of these molecules were evaluated based on Lipinski’s Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and compared with known drugs. Additionally, we synthesized these target molecules (7a–7s) using Suzuki-Miyaura coupling with a nickel catalyst replacing palladium. The chemical structures of the synthesized compounds were confirmed through elemental analysis, LC-MS,1H-NMR, and 13C-NMR spectroscopy.

Novel indole based fused triazole-thiadiazole derivatives as anti-diabetic agents: in vitro and in silico approaches.

Aim: The current research presents novel library of indole derived fused triazole-thiadiazole derivatives (1-17) for treatment of diabetes mellitus.Methods & results: These compounds were synthesized by treating 2-(1H-indol-3-yl)acetic acid with hydrazinecarbothiohydrazide followed by treating the resultant compound with substituted benzoic acid. Structural validation was achieved spectroscopically (1HNMR, 13CNMR and HREI-MS). The synthesized compounds were subjected to biological evaluation to assess their potential as anti-diabetic. Molecular docking study was employed to investigate the binding interactions of these analogs with relevant proteins. ADMET analysis was used to predict their drug-like properties. Notably, compound-10 (IC50 = 1.27±1.25 and 2.18±2.45 μM) bearing para-substituted F atom exhibited the highest potency due to strong inhibitory interactions through hydrogen bonding.Conclusion: This study identifies promising compounds with anti-diabetic activity, paving the way for the treatment of diabetes mellitus.

Causal associations of tea consumption on risk of pancreatic adenocarcinoma and the mediating role of vascular endothelial growth factor D levels.

Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.

Screening for antimicrobial and antioxidant activities of quinazolinone based isoxazole and isoxazoline derivatives, synthesis and In silico studies.

Two novel series of quinazolinone based isoxazole and isoxazoline hybrid compounds were synthesized from 6-aminoquinazolinone as a key precursor. The title compounds were achieved in synthetic routes via propargylation and allylation reactions of the precursor followed by cyclization with various chloroximes. The new compounds 4a-g and 6a-g were screened for their antimicrobial activity against two Gram-positive bacteria, two Gram-negative bacteria and two fungi by employing Ampicillin and Itraconazole as standard reference. Among all, the 4-bromosubstituted analogues in isoxazole series 4d and in isoxazoline series 6d demonstrated potent activity against all bacterial and fungal strains compared to Ampicillin as well as Itraconazole. The MIC of these compounds were determined as 0.012μM. The antioxidant investigation revealed that compounds 4f and 6f with dimethyl substitution, exhibited significant activity. Their respective IC50 values were 1.28 ± 0.33, 1.39 ± 0.38µM and 1.07 ± 0.24, 1.10 ± 0.26µM, when compared to Ascorbic acid. The compounds 4g and 6g with dichloro substitution, exhibited promising results with IC50 values were 2.72 ± 0.34µM and 2.78 ± 0.41µM for 4g, and 2.24 ± 0.93µM and 2.45 ± 0.53µM for 6g, respectively. Their antimicrobial and antioxidant activities were authenticated by the molecular docking study against crystal structure of DNA gyrase and NADPH oxidase. The predicted ADME properties of these molecules progressed favourable drug-likeness properties.

Phytochemical profiling, spectroscopic identification of active compounds, and mechanism of the anticandidal properties of Datura stramonium L. using SwissADMET prediction and molecular docking analysis

BackgroundDatura stramonium L., a wild-growing herb, has been traditionally used to treat various ailments, including toothache, asthma, rheumatism, epilepsy, and alopecia. Scientific evidence supports its anticancer, anti-inflammatory, anti-asthmatic, anticholinergic, antifungal, and antibacterial properties. AimThis study aimed to isolate, characterize, and identify the most potent anticandidal compounds inhibiting the growth of Candida spp., while also predicting their drug-likeness and toxicity profiles. MethodThe anticandidal activity of D. stramonium leaf extracts was assessed using the Agar well-diffusion method and minimum inhibitory concentration (MIC) was determined by the broth dilution method. The most active extract was selected for column chromatography. Different fractions were collected and screened against pathogenic Candida spp. The most active fraction was subjected to Gas chromatography-Mass spectrometry (GC-MS), Fourier Transform-Infrared Spectroscopy (FT-IR), and Nuclear Magnetic Resonance (NMR) analysis. Additionally, computational tools such as molecular docking and ADMET prediction provided further insights into the molecular interactions between the target enzymes. ResultsIn vitro anticandidal activity demonstrated that the ethyl acetate extract exhibited significant activity against human pathogenic Candida spp., with the highest zones of inhibition against Candida guilliermondii (20.33±0.56 mm), Candida tropicalis (16.33±0.58 mm), and Candida albicans (14.66±1.05 mm), with a minimum inhibitory concentration (MIC) value of 25 ug/ml. Additionally, the most potent fraction (F8) obtained from the Column revealed significant anticandidal activity. GC-MS analysis of the F8 fraction indicated the presence of 23 compounds, with the major compounds being Phthalic acid, di(2-propylpentyl) ester (Compound 1), Pentadecane (Compound 2), Octadecane (Compound 3), Benzoic acid, 3-Amino-5-Hydroxy-, Methyl ester (Compound 4), and 1,2-Benzenedicarboxylic acid, bis (2-ethylhexyl) ester (Compound 5). This study reports all 23 compounds from D. stramonium for the first time. Furthermore, NMR studies confirmed the presence of Phthalic acid, di(2-propylpentyl) ester as the most abundant compound, designated as compound 1. Finally, docking analysis revealed that compound 1 showed good binding affinities for the tested enzymes, with the highest binding scores of -7.084 Kcal/mol and -7.030 Kcal/mol with Lanosterol 14-alpha demethylase (PDB ID: 5JLC, 5TZ1). The results of the in silico pharmacokinetic and drug-likeness properties indicated that compound 1 is a potential anticandidal drug candidate. ConclusionThis study highlights that 23 compounds were reported from the leaf extract of D. stramonium for the first time. The findings suggest that compound 1 can be considered a new anticandidal drug candidate.