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Ajuga orientalis, a perennial herb from the Lamiaceae family, is traditionally used in Jordanian folk medicine for its therapeutic properties. This study evaluates the phytochemical profile, cytotoxicity, drug‐likeness, and molecular docking of the methanolic extract of A. orientalis to explore its potential as a source of novel therapeutic agents. GC‐MS analysis identified 21 compounds, including oleic acid methyl ester (27.1%) and palmitic acid (12.5%). The extract demonstrated significant concentration‐dependent cytotoxicity against RAW264.7 macrophage cells, with an IC50 of 91.5 µg/mL. Molecular docking studies revealed fundamental interactions of phytochemicals with cancer‐related proteins, including VEGFR2 and TLR4/MD‐2, showing strong binding affinities. Notably, 1,7‐di(2,5‐dimethylphenyl)‐2,2,4,4,6,6‐hexamethyl‐1,3,5,7‐tetraoxa‐2,4,6‐trisilaheptane and the 2TBDMS derivative of 4‐hydroxybenzeneacetic acid exhibited promising interactions, indicating potential for inhibiting angiogenesis and modulating immune responses. Drug‐likeness evaluation of 18 compounds showed that 11 meet the criteria for oral bioavailability, though some challenges for drug development remain. This research underscores the therapeutic potential of A. orientalis compounds in cancer treatment and immune modulation, suggesting further experimental validation and development of these bioactive compounds. [ABSTRACT FROM AUTHOR]

Dendrimers are polymeric compounds which exhibit notable advantages, particularly in medicinal chemistry. The therapeutic potential of these molecular architectures can be screened through in silico method which facilitates the identification of the ones with the highest potential for further investigation. Here, we have reported the in silico investigation of a series of dendritic architecture based on para‐substituted aniline. Density functional theory (DFT) method was employed to optimize the structures and to analyze the quantum chemical parameters. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was additionally assessed, which unveiled favorable drug‐like characteristics and moderate to good bioactivity across all compounds. Utilizing the drug‐likeness property in machine learning techniques, the potential for predicting novel drug‐like dendrimers was explored. [ABSTRACT FROM AUTHOR]

In this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Computational modelling and simulation have made it possible to considerably advance in the exploration of conformational and dynamical features of the desired compound. It not only assists in the interpretation of the experimental result, but also to provide insights about the internal motions of the molecule at the atomic level. In this work, Density Functional Theory calculations are performed to replicate the experimental electronic structure of 2C4H5ClN4.C4H6O4, and its nature is discussed in detail. The B3LYP/6‐311++G(d,p) basis set applied to evaluate the optimal structure characteristics resulted in revealing the corresponding chemical, physical, and biological properties of the molecule. The energy exchange between the contributor and receiver are examined by Natural Bond Orbital analysis. Based on frontier molecular orbitals analysis, the obtained minimum energy gap (0.199 eV) value ensures the stability of the title compound. The molecular electrostatic potential mapping predicts the electrophilic and nucleophilic charge distributions on the molecule. The 3D topology of the crystal packing is analyzed and interpreted via the energy‐framework simulation studies using CystalExplorer software. Through the In‐silico‐ADME calculations, the drug‐likeness and physicochemical properties of the molecule is predicted. Furthermore, the molecular docking studies are used to determine the bioactivity and anti‐diabetic properties of the title compound. [ABSTRACT FROM AUTHOR]

Imidazopyridine scaffold holds significant pharmacological importance in the treatment of cancer. An in‐house synthesized imidazopyridine‐based molecule was found to have promising anticancer activity against breast cancer, lung cancer, and colon cancer. The molecule is an inhibitor of pyruvate kinase M2, the enzyme that elevates tumor growth, metastasis and chemoresistance by directly controlling tumor cell metabolism. Screening of the physicochemical properties of any lead molecules is essential to avoid failure in late‐stage drug development. In this research, the physicochemical properties of the molecule including log P, log D, pKa, and plasma protein binding were assessed to check its drug‐likeness. Plasma and metabolic stability of the molecule were also evaluated. Moreover, pharmacokinetic profiles of the lead molecule in Sprague‐Dawley rats and in vitro metabolite identification studies were also performed. Finally, an in silico software, Pro‐Tox‐II, was used to predict toxicity of the molecule and its metabolites. Log P, Log D (pH 7.4), pKa, and plasma protein binding of the molecule were found to be 2.03%, 2.42%, 10.4%, and 98%, respectively. The molecule was stable in plasma and metabolic conditions. A total of nine new metabolites were identified and characterized. Cmax and t½ of this molecule were found to be 4016 ± 313.95 ng/mL and 9.57 ± 3.05 h, respectively. Based on the previously reported study and this finding, the molecule can be considered as a promising anticancer lead with potential drug‐likeness properties. Further preclinical and clinical drug discovery studies may be initiated in continuation of this study in search of a potential anticancer lead. [ABSTRACT FROM AUTHOR]

The high expression of anti‐apoptotic Bcl‐2 protein in cancer cells can confer resistance to apoptosis, allowing cells to evade cell death signals and continue proliferating. Therefore, Bcl‐2 has become a crucial target for cancer therapy. In this work, we looked for new drugs targeting Bcl‐2 that can induce apoptosis in cancer cells and improve treatment effectiveness like chemotherapy. In silico approaches, such as molecular docking, were used to identify potential new drugs by screening the Enamine collection (HLL‐460) against two conformations of the Bcl‐2 protein obtained by molecular dynamics (MD) simulations. Molecular docking was focused on two specific sites of Bcl‐2; the binding groove and the flexible loop domain (FLD), which play an essential role in regulating the apoptotic process. Compounds with docking scores less than those of the reference drugs (Venetoclax and Taxol) were selected. They were analyzed by PASS online, which predicted putative anti‐cancer properties for ten compounds; of these, three candidates targeted binding groove, five to FLD, and two can bind to both sites; these compounds were selected and analyzed. The drug‐like properties of the ten compounds passed Lipinski's rules, their pharmacokinetic profiles were excellent, safe, and had potential anti‐neoplastic activity. [ABSTRACT FROM AUTHOR]

Medium sized molecules such as peptides and macrocycles have recently drawn much attention as potent sources of medicinal lead compounds, whereas the possibility of obtaining a practical drug from them remains limited. The present paper describes a concept of discovering novel medicinal targets or binding modes as well as lead compounds by the one‐peptide‐on‐one‐bead (OPOB) technology for comprehensive screening. The difficulty and problems in conventional drug discovery methods that generally deal with one predetermined target are considered. The building blocks used for the present libraries were selected based on previous results in development of peptidic drugs. Each constituent has the common structure of cyclic form prepared by disulfide of cysteinyl residues or thioether linkages, additionally a methionine residue was inserted for the site‐specific rapid cleavage by cyanogen bromide to liberate the immobilized peptides allowing reliable characterization by MALDI‐TOF‐MS/MS without LC‐purification. Thus, a high throughput construction method for cyclic peptide libraries as well as characterization of single bead are proposed for drug discovery. [ABSTRACT FROM AUTHOR]

Thiazolidin‐4‐one is a versatile nucleus that has been reported to exhibit a diverse array of biological activities, including anticancer and antimicrobial activities. In the current research study, a series of C2‐(p‐substituted phenyl)‐thiazolidin‐4‐one compounds conjugated with anilines were designed and tested for drug‐likeness behaviour. Subsequently, the designed compounds were synthesized, characterized, and tested for anticancer activity against three cancer cell lines, namely liver (HEP−G2 cells), breast (MDA‐MB‐231), and glioblastoma (U87MG cells), with gemcitabine as the reference positive control drug. Initially, the compounds were tested at 50 micromolar, while the MIC was determined for the selected active compounds. Among the three cell lines, MDA‐MB‐231 showed relatively higher sensitivity towards the tested compounds. Four compounds of the series exhibited comparable or superior cytotoxicity to the reference drug gemcitabine. Particularly, N‐(p‐tolyl)‐2‐(2‐(4‐methoxyphenyl)‐4‐oxothiazolidin‐3‐yl)acetamide (6 d) displayed highest cytotoxicity among the series. The anticancer activity of the selected compounds was also tested against 3D spheroid models, in which compound N‐(4‐chlorophenyl)‐2‐(2‐(4‐methoxyphenyl)‐4‐oxothiazolidin‐3‐yl)acetamide (6 a) induced apoptosis in brain tumour spheroids (MTS). Docking studies of compound 6 d were performed against different targets, namely dihydrofolate reductase, phosphoinositide 3‐kinase, epidermal growth factor receptor, dihydroorotate dehydrogenase, and murine double minute 2, which illustrated inhibition of dihydroorotate dehydrogenase as a possible mechanism of toxicity. The compounds were also evaluated in vitro for antibacterial activity against two bacterial strains (E. coli and P. aeruginosa) and a Candida albicans fungal strain. [ABSTRACT FROM AUTHOR]

This study examines how two popular drug‐likeness concepts used in early development, Lipinski Rule of Five (Ro5) and Veber's Rules, possibly affected drug profiles of FDA approved drugs since 1997. Our findings suggest that when all criteria are applied, relevant compounds may be excluded, addressing the harmfulness of blindly employing these rules. Of all oral drugs in the period used for this analysis, around 66 % conform to the RO5 and 85 % to Veber's Rules. Molecular Weight and calculated LogP showed low consistent values over time, apart from being the two least followed rules, challenging their relevance. On the other hand, hydrogen bond related rules and the number of rotatable bonds are amongst the most followed criteria and show exceptional consistency over time. Furthermore, our analysis indicates that topological polar surface area and total count of hydrogen bonds cannot be used as interchangeable parameters, contrary to the original proposal. This research enhances the comprehension of drug profiles that were FDA approved in the post‐Lipinski period. Medicinal chemists could utilize these heuristics as a limited guide to direct their exploration of the oral bioavailability chemical space, but they must also steer the wheel to break these rules and explore different regions when necessary. [ABSTRACT FROM AUTHOR]

The recent incidence of terrible acute respiratory syndrome coronavirus 2 (SARS CoV‐2) has presently experienced some noteworthy mutations since its discovery in 2019 in Wuhan, China. The present research work focuses on the synthesis of three triazole derivatives (BMTPP, BMTTP, and BMTIP) and their inhibition activities against SARS‐Cov‐2 spike and ACE2 receptor proteins. The crystal structure for BMTTP was determined by the SCXRD method and optimized geometrical parameters for the three triazole derivatives were obtained by DFT calculations. HOMO‐LUMO, Global reactive descriptors [GRD], and Molecular electrostatic potential (MEP) investigations exposed that all three compounds have biological properties. The drug‐likeness ability of the synthesized compounds was examined using Molinspiration and a pre‐ADMET online Server. Further, to explore the binding nature of three synthesized compounds with SARS‐Cov‐2 spike proteins/ACE2 receptor molecular docking studies were executed. The outcomes we obtained from molecular docking simulation studies suggest that the synthesized triazole derivatives may be well utilized as curing medicines against COVID‐19. Ultimately, animal tests and precise clinical tests are required to prove the potent nature of these compounds against COVID‐19. Finally, the present outcomes must be proved to utilize in‐vitro and in‐vivo antiviral methods. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the molecular design and drug development of PROTACs is efficient identification of potent and drug‐like degraders. This review aims to comprehensively summarize and analyse state‐of‐the‐art methods and strategies in the design of PROTACs. We provide a detailed illustration of the general principles and tactics for designing potent PROTACs, highlight representative case studies, and discuss the advantages and limitations of these strategies. Particularly, structure‐based rational PROTAC design and emerging new types of PROTACs (e.g., homo‐PROTACs, multitargeting PROTACs, photo‐control PROTACs and PROTAC‐based conjugates) will be focused on. [ABSTRACT FROM AUTHOR]

Infectious diseases of bacteria and fungi have become a major risk to public health because of antibiotic and antifungal resistance. However, the availability of effective antibacterial and antifungal agents is becoming increasingly limited with growing resistance to existing drugs. In response to that, novel agents are critically needed to overcome such resistance. A new series of 6‐hydroxyquinolinone 3, 4, 5a, 5b, 6a and 6b bearing different side chains were synthesized and evaluated as antimicrobials against numbers of bacteria and fungi, using inhibition zone technique. As one of these derivatives, compound 3 was identified as a potent antibacterial and antifungal agent against all tested microorganisms with good minimum inhibitory concentration values comparable to reference drugs. Molecular docking studies were performed on antibacterial and antifungal targets; microbial DNA gyrase B of Staphylococcus aureus (PDB ID: 4URO); N‐myristoyltransferase of Candida albicans (PDB ID: 1IYK), respectively, to predict the most probable type of interaction at the active site of the target protein in addition to binding affinities and orientations of docked ligands. Additionally, in silico prediction in terms of detailed physicochemical ADME and toxicity profile relating drug‐likeness as well as medicinal chemistry friendliness was performed to all synthesized compounds. The results indicated that a novel 4,6‐dihydroxyquinolin‐2(1H)‐one (3) is likely to be a newly synthesized drug candidate, indicating low toxicity in addition to good in silico absorption. In order to pave the way for more logical production of such compounds, structure–activity and toxicity relationships are also discussed. [ABSTRACT FROM AUTHOR]

Tuberculosis is one of the leading cause of death worldwide and Mycobacterium tuberculosis still remains to be the fatal human pathogen. In pursuit of novel diphenyl ethers as antitubercular and antibacterial agents, a series of novel substituted N‐(3‐hydroxy‐4‐phenoxybenzyl)‐N‐phenylmethanesulfonamides 4 a‐k were rationally designed, synthesized and evaluated for their in vitro antitubercular and antibacterial activities. Compounds 4 j and 4 d appeared to be the most promising against Mycobacterium tuberculosis strain H37Rv with minimum inhibitory concentration (MIC) of 42 μM and 65 μM, respectively. Compound 4 j exhibited good in vitro antibacterial activity with MIC of 6.97 μM, 13.94 μM, and 27.88 μM against Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa respectively, indicating it's broad‐spectrum of activity. The safety profile of the compounds was assessed on HepG2, Vero and RAW 264.7 cell lines. Molecular docking and molecular dynamics simulation studies were performed to study the binding behavior of the compounds. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic disease characterized by autoimmunity, joint inflammation, and cartilage destruction, which affects 0.5-1% of the population. Many compounds from herbal medicines show the potentials to treat RA. On this basis, the compounds with good pharmacokinetic behaviors and drug-likeness properties will be further studied and developed. Therefore, the herbal compounds with anti-RA activities were reviewed in this paper, and the cheminformatics tools were used to predict their drug-likeness properties and pharmacokinetic parameters. A total of 90 herbal compounds were analyzed, which were reported to be effective on RA models through anti-inflammation, chondroprotection, immunoregulation, antiangiogenesis, and antioxidation. Most of the herbal compounds have good drug-likeness properties. Most of the compounds can be an alternative and valuable source for anti-RA drug discovery. [ABSTRACT FROM AUTHOR]

A series of Amantadine‐based azo Schiff base dyes 6a–6e have been synthesized and characterized by 1H NMR and 13C NMR and evaluated for their in vitro carbonic anhydrase II inhibition activity and antioxidant activity. All of the synthesized showed excellent carbonic inhibition. Compound 6b was found to be the most potent derivative in the series, and the IC50 of 6b was found to be 0.0849 ± 0.00245 μ m (standard Acetazolamide IC50 = 0.9975 ± 0.049 μ m). The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 6b is interacting by making two hydrogen bonds w at His93 and Ser1 residues, respectively. All compounds showed a good drug score and followed Lipinski's rule. In summary, our studies have shown that these amantadine‐derived phenolic azo Schiff base derivatives are a new class of carbonic anhydrase II inhibitors. [ABSTRACT FROM AUTHOR]

Earlier studies have shown that CYP3A4 inhibition is influenced by lipophilicity, size and fMF, where fMF is the size of the molecular framework divided by the total size of the molecule. Other previous studies have shown that there is an enrichment of compounds with only one ring system among drugs in comparison to clinical candidates and general bioactive compounds as well as enrichment among natural products and human metabolites compared to general bioactive compounds. Thus a logical extension of the earlier investigations would be to study how ring systems influence CYP3A4 inhibition. It is shown here that compounds with only one ring system have lower CYP3A4 inhibition compared to compounds with several ring systems. The reason therefore is that they are both smaller and have smaller fMF values compared to compounds with several ring systems. The investigation provides additional insights into how a molecule should be constituted to have low CYP3A4 inhibition and may influence library design and compound acquisitions. [ABSTRACT FROM AUTHOR]

A series of Ni (II), Co (II) and Cu (II) complexes were synthesized with excellent yields via a one‐pot ball milling chelation reaction of those metals and β‐diketone. The process offers numerous advantages, such as better yield, short reaction time and mild reaction conditions. The computational studying was estimated to approve the geometry of the isolated solid compounds by applying density functional theory. The synthesized compounds were interpreted by using various spectroscopic techniques [infrared (IR), 1H‐NMR, 13C‐NMR, UV–visible, electron spin resonance (ESR) and mass spectrometry] together with some physical studies (molar conductance and magnetic susceptibility). The outcomes data displayed that the (HD1), (HD2) and (HD3) acted as neutral and/or mononegative bidentate ligands. The ESR as well as electronic spectra suggested the octahedral configuration for all isolated complexes, expect [Cu (HD2)(OAc)2]·2H2O has square planar structure. Also, the in vitro antimicrobial assay was done by using the well diffusion method for HD1, HD2, HD3 and their complexes. Synthesis of diketone compounds by ball milling.Spectroscopic characterization (IR, 1H‐NMR, 13C‐NMR, UV–visible, ESR and MS).Studying the geometry of isolated compounds by DFT method. [ABSTRACT FROM AUTHOR]