Compound 3b Research Articles

Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study.

The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse β-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.

DFT studies on N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl)

In this work, molecular descriptors of N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl) halogenated benzamides (1a-h) have been computed using a quantum chemical technique through DFT. Prior work involved the synthesis of compounds (1a-h) and the assessment of their anticancer activity on breast, colon, and liver tumors: MCF-7, HCT-116, and HepG-2 cell lines respectively. Since 1a, 1b, and 1d showed the most potential anticancer impact, their ability to inhibit EGFRWT was investigated. Based on the biological data, 1b inhibited EGFRWT the most. According to the docking evaluation, an H-bond with the threonine residue was one of the main non-covalent contacts between 1b and the EGFRWT active site residues. PES, MESP, HOMOs, LUMOs, energy band gap, global reactivity indices [electron affinity (A), ionization energies (I), electrophilicity index (ω), nucleophilicity index (ε), chemical potential (μ), electronegativity (χ), hardness (η), and softness (S)], condensed Fukui functions, NBO, and NCIs are the molecular descriptors of 1a-h that were computed using DFT technique. According to the theoretical investigation results, compounds (1a-h) might have anticancer effects; these findings are consistent with the biological findings from our previous research. Compound 1b had the lowest binding energy, according to an assessment of the binding energies between the threonine and the three most active compounds (1a, 1b, and 1d). This is consistent with the outcomes of the docking study and the biological examination of the influence of 1a, 1b, and 1d on EGFRWT.

Chiral thioureas containing naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, cholinesterase inhibition activity and molecular docking studies

Butyrylcholinesterase (BChE), which plays a role in the regulation of acetylcholine (ACh) as well as cholinergic type neurotransmission, also has non-cholinergic functions such as differentiation, proliferation and apoptosis. The strategy of increasing ACh levels without the typical undesirable effects of AChE inhibitors used in treatment with selective inhibition of BChE may be an effective approach to delay the progression of Alzheimer's disease (AD). Based on this approach, twenty derivatives of chiral thioureas containing the naphthalene moiety (1a-10a and 1b-10b) in both enantiomeric forms were designed, synthesized with good yields (up to 90 %), in this study. Also, their AChE and BChE inhibition activities and antioxidant profiles were tested. All chiral thioureas except compound 5b showed excellent inhibitory activity against BChE but lower inhibitory activity against AChE compared to galantamine. The activity results on BChE revealed that compound 1b (S-enantiomer) had the strongest inhibitory effect on BChE (IC50 = 10.18 ± 1.02 μM) with a selectivity index of 7.27 among all compounds. In terms of antioxidant activity, compound 7a (R-isomer) exhibited the overall highest antioxidant profile in the series of chiral thioureas. Molecular docking studies were used to reveal the interactions of the most active compounds with target enzymes. Besides, an estimation of the drug-likeness and pharmacokinetic properties of all chiral thioureas was performed.

Synthesis, spectroscopic analysis, molecular docking and DFT study of novel 1,2,3-Triazole derivatives incorporating paramethoxythymol and salicylaldehyde moieties

This study investigates the synthesis, characterization, and computational analysis of novel paramethoxythymol-1,2,3-triazole derivatives derived from naturally occurring thymol. HRMS and NMR spectroscopy (1H and 13C) were meticulously employed to ensure precise identification of the synthesized compounds. Density functional theory (DFT) calculations were performed to elucidate the stability of the derivatives. In silico docking simulations, molecular dynamics, and ADMET analysis provided insights into the potential interactions between the synthesized molecules and the active sites of Epidermal Growth Factor Receptor (EGFR) and B-cell lymphoma 2 (Bcl2). Docking analysis revealed favorable binding affinities of the 1,2,3-triazole derivatives towards EGFR, with compound 5b exhibiting the most potent interaction, characterized by a docking score of -28.8 kJ/mol. Conversely, compound 6b demonstrated a docking score of -29.2 kJ/mol with Bcl2. Molecular dynamics investigations indicated that the complex between Bcl2 and compound 5b is more stable, suggesting it as a potential candidate for inhibiting Bcl2 protein. These findings suggest that paramethoxythymol-1,2,3-triazole derivatives hold promise as lead candidates for the development of novel targeted anticancer agents.

FeCl3 induced sonochemical heteroarylation: Synthesis of meridianin alkaloid analogues for their in silico/in vitro evaluation against SIRT1

Meridianins A − G, the indole based marine alkaloids have displayed a diverse range of biological properties including anti-cancer / anti-tumour activities. Based on reported correlation between anticancer activities and SIRT1 inhibition, the meridianin alkaloid analogues were explored as possible inhibitors of SIRT1. The FeCl3 mediated regioselective heteroarylation under ultrasound irradiation was employed for the synthesis of this class of N-heterocycles. The methodology involved CC bond forming reaction between 2-amino-4-chloropyrimidine and indole to afford a library of desired compounds in varied yield depending on nature of substituent present on the reactant indole. Indeed the product yield was decreased when the NO2 or OH or two chloro groups were present on the indole ring. The usefulness of the current approach was demonstrated via functionalization of one of the synthesized compound i.e. Meridianin G under ultrasound. All the synthesized compounds were characterized by 1H and 13C NMR and MS spectral data. When docked into the SIRT1 in silico, promising interactions with this protein were noted for some of the meridianin analogues synthesized in addition to their probable selectivity towards SIRT1 over SIRT2. The common interacting residues of SIRT1 were found to be VAL412, PHE413, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, PHE273 and PHE297. Indeed, the top four compounds e.g. 3b, 3c, 3d and 3f participated in H-bond interactions through their indole “NH” and the primary amino group with ASN346, HIS363 and VAL412 of SIRT1. Correlating the findings of in silico studies, these compounds showed promising inhibition of SIRT1 in vitro with IC50 ∼2.9–3.7 µM when 3f emerged as the best active molecule. The SAR (Structure-Activity-Relationship) analysis suggested high to good activities for the NO2, Cl, Br or MeO group at C-5 of indole ring (due to participation of these groups in H-bonding interaction as noted during the in silico docking studies) whereas a free NH moiety of the indole ring was essential for activity. The in silico and in vitro studies along with ADME predictions suggested that compound 3b, 3c, 3d and 3f could be of further pharmacological interest.

Microwave-assisted click synthesis, characterisation, and In silico studies of novel 2H-chromene-1,2,3-triazolyl glycoconjugates as potent anticancer and antibacterial agents

A series of novel 2H-chromene-1,2,3-triazolyl glycoconjugates 10a-w were synthesized, well characterized and evaluated for their in vitro antimicrobial and anticancer activities. Among the tested compounds, 10a, 10b, 10u, 10v, and 10w exhibited the most excellent potency against both gram-positive (S. aureus) and gram-negative (E. coli) bacterial strains relative to the standard drug, Gentamicin. The anticancer results showed that in MCF-7 cell line all the tested compounds exhibited better activity as compared to other two cancer cell lines (MDA-MB-231 and A549). Compounds 10t, 10u, 10v, and 10w showed significant cytotoxicity against MCF-7 cell line. The molecular docking studies suggested that all the four potent compounds exhibited a greater affinity for the selected receptors. Experimentally and computationally observed structure-activity relationships indicates, -OCH3 group at R2 position in benzopyran ring with tosyl-protected sugar containing compound 10b and benzyl-protected sugar containing compound 10t enhanced the antibacterial and anticancer activity respectively. Frontier molecular orbital analysis of compounds using the global reactivity parameters indicated that benzyl-protected sugar and acetyl-protected sugar containing compounds are stable and exhibits low reactivity. Moreover, molecular electrostatic potential analysis plots clearly showed that the compounds have strong electrophonic reaction potential. Moreover, the assessment of ADMET predictions revealed favourable pharmacokinetic properties of the investigated compounds. Collectively, it was observed that compounds 10u, 10v, and 10w could be considered as promising dual anticancer antibiotic inhibitors.

Design and synthesis of new benzoxazole derivatives and study of their interactions with a G4 model by UV spectroscopy and in silico methods

In this study, we synthesized novel benzoxazol-2-ylmethyl-(1H-1,2,3-triazol-4-yl)phenyl)-3-aminopropanamides (6a-d) in high yields by means of the Copper-catalysed Azide-Alkyne Cycloaddition (CuAAC) reaction. The synthetic pathway involves the conversion of 2-aminophenol to 2-(bromomethyl)benzoxazole 1, followed by its transformation into the azide derivative 2. Subsequent reaction with functionalized arylalkynes 5a-d under Sharpless’s reaction conditions yields the desired compounds 6a-d. These benzoxazoles were then evaluated as G-Quadruplex DNA (G4) ligands by UV spectroscopy studies using a telomeric sequence (Tel22) as G4 model. We studied how the absorbance at λmax varies over time for the 6a-d/Tel22 mixtures at different molar ratios. Moreover we carried out melting experiments in order to point out any possible stabilization effects arising by ligand interaction. Our findings indicate that Tel22 is slighlty but significantly stabilized by compound 6b at a 1:1 ratio. Furthermore for 6b, these results align well with in silico predictions suggesting that the ligand acts as groove binder interacting with six guanosine residues of the telomeric model.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Design, synthesis and biological Evaluation of novel chromones having 3,4-dihydropyrimidin-2(1H)-one core at C-8 in combination with triazoles: New α-glucosidase inhibitors and anti-bacterial agents

The Biginelli reaction synthesizes dihydropyrimidones through a multi-component reaction. A β-ketoester, aldehyde, and urea or thiourea react in the presence of an acid catalyst to form these dihydropyrimidones. 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids (9a-9l) were synthesized by multiple steps including one pot Biginelli multicomponent reaction depicted in the scheme. An efficient method for the Biginelli reaction of Chromone aldehyde, acetoacetate esters, and urea employed in the presence of ferric chloride is described. In the end, we have successfully synthesized twelve derivatives of 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids and subjected them to testing for Antibacterial activity and α-glucosidase inhibition activity. Among these derivatives, compound 9g (IC50 = 142.92 nmol) and 9e (144.49 nmol) exhibited significant inhibitory activity in comparison to the positive control acarbose (IC50 = 350.91 nmol). Compound 9g demonstrated the most significant suppression against Escherichia coli and Bacillus cereus, with zone diameters of 8.8 ± 1.35 mm and 9.1 ± 0.23 mm, respectively. Compound 9b displayed a clear area where bacterial growth was inhibited, measuring 7.5 ± 1.25 mm against Klebsiella pneumonia. Compound 9k exhibited a zone of inhibition measuring 8 ± 1.2 mm in radius against Staphylococcus epidermidis. The docking results for the synthesized compounds indicate that compound 9b exhibited the most favorable docking score of −10 kcal/mol, whereas compound 9a had the second-best docking score of −8.7 kcal/mol. Molecular docking was utilized to examine the interactions between the title compounds and α-glucosidase, in order to provide valuable insights. The data obtained revealed significant interactions that contribute to the inhibitory effects of the drugs against α-glucosidase. These compounds exhibit significant potential as attractive initial candidates for the development of new α-glucosidase inhibitors.

Synthesis, COX-2 inhibition, anti-inflammatory activity, molecular docking, and histopathological studies of new pyridazine derivatives

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1β. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Crystal structures of four thio-glycosides involving carbamimido-thio-ate groups.

The compounds 2',3',4',6'-tetra-O-acetyl-β-d-gluco-pyranosyl N'-cyano-N-phenyl-carbamimido-thio-ate (C22H25N3O9S, 5a), 2',3',4',6'-tetra-O-acetyl-β-d-galacto-pyranosyl N'-cyano-N-phenyl-carbamimido-thio-ate, (C22H25N3O9S, 5b), 2',3',4',6'-tetra-O-acetyl-β-d-galacto-pyranosyl N'-cyano-N-methyl-carbamimido-thio-ate (C17H23N3O9S, 5c), and 2',3',4',6'-tetra-O-acetyl-β-d-galacto-pyranosyl N'-cyano-N-p-tolyl-carbamimido-thio-ate (C23H27N3O9S, 5d) all crystallize in P212121 with Z = 4. For all four structures, the configuration across the central (formal) C=N(CN) double bond of the carbamimido-thio-ate group is Z. The torsion angles C5-O1-C1-S (standard sugar numbering) are all close to 180°, confirming the β position of the substituent. Compound 5b involves an intra-molecular hydrogen bond N-H⋯O1; in 5c this contact is the weaker branch of a three-centre inter-action, whereas in 5a and 5d the H⋯O distances are much longer and do not represent significant inter-actions. The C-N bond lengths at the central carbon atom of the carbamimido-thio-ate group are almost equal. All C-O-C=O torsion angles of the acetyl groups correspond to a synperiplanar geometry, but otherwise all four mol-ecules display a high degree of conformational flexibility, with many widely differing torsion angles for equivalent groups. In the crystal packing, 5a, 5c and 5d form layer structures involving the classical hydrogen bond N-H⋯Ncyano and a variety of 'weak' hydrogen bonds C-H⋯O or C-H⋯S. The packing of 5b is almost featureless and involves a large number of borderline 'weak' hydrogen bonds. In an appendix, a potted history of wavelength preferences for structure determination is presented and it is recommended that, even for small organic crystals in non-centrosymmetric space groups, the use of Mo radiation should be considered.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Design, Synthesis, Nematicidal Evaluation, and Molecular Docking Study of Pyrano[3,2-c]pyridones against Meloidogyne incognita.

Root-knot nematodes pose a serious threat to crops by affecting production and quality. Over a period of time, substantial work has been done toward the development of effective and environmentally benign nematicidal compounds. However, due to the inefficiencies of previously reported synthetics in achieving the target of safe, selective, and effective treatment, it is necessary to develop new efficacious and safer nematicidal agents considering human health and environment on top priority. This work aims to highlight the efficient and convenient l-proline catalyzed synthesis of pyrano[3,2-c]pyridone and their use as potential nematicidal agents. In vitro results of larval mortality and egg hatching inhibition revealed maximum nematicidal activity against Meloidogyne incognita from compounds 15b, 15m, and 15w with LC50 values of 28.8, 46.8, and 49.18 μg/mL at 48 h, respectively. Under similar conditions, pyrano[3,2-c]pyridones derivatives 15b (LC50 = 28.8 μg/mL) was found at par with LC50 (26.92 μg/mL) of commercial nematicide carbofuran. The in vitro results were further validated with in silico studies with the most active compound 15b nematicidal within the binding to the pocket of acetylcholine esterase (AChE). In docking, binding free energy values for compound 15b were found to be -6.90 kcal/mol. Results indicated that pyrano[3,2-c]pyridone derivatives have the potential to control M. incognita.

Chiral (S)-BINOL-phosphates: Design, synthesis and their antibacterial and α-glucosidase inhibition studies

A new series of chiral (S)-BINOL-derived phosphoric acid derivatives (8a-k) with 3,3′-disubstitution were successfully synthesized under microwave irradiation, yielding high product quantities within a short reaction time. The antibacterial and α-glucosidase inhibitory properties of these compounds were evaluated. Notably, compound 8b exhibited remarkable antibacterial efficacy against B. subtilis, S. aureus, S. epidermidis, P. aeruginosa, and K. pneumoniae, with a MIC value of 1.17 g mL−1. Furthermore, the electron-withdrawing nitro group-containing derivative, 8d displayed potent antibacterial activity (MIC = 1.17 g mL−1) against B. subtilis, S. epidermidis, and E. coli. Among the synthesized compounds, compound 8b, containing chloro substitutions at the 3,5-positions of the phenyl groups in (S)-3,3′-disubstituted BINOL, demonstrated the most noteworthy α-glucosidase inhibitory activity with IC50 value of 2.067 ± 0.017 M.

Exploitation of ninhydrin core towards spiropyranocoumarin and benzofuranyl coumarin: Synthesis, crystal structure and self-assembly

Pyrano and furanocoumarins are oxygen-containing heterocycles frequently found in natural products and biologically active molecules. In the present work, ninhydrin core is employed for the first time as the pivotal framework to construct benzopyrano/furano coumarin skeleton. It has been found that substrates like phenol, p-/m-cresol, m-methoxyphenol, p-chlorophenol etc. reacted with ninhydrin-4-hydroxycoumarin adduct 3 in AcOH/H2SO4 to furnish a new class of spiropyranocoumarins 5a-f via condensation/cyclization sequence. Under similar conditions, reaction of adduct 3 with 3,5-dihydroxybenzoic acid delivered benzofuranyl coumarin 6 through ring closing/ring opening mechanism. Structures of the synthesized compounds were characterized by IR, 1H and 13C NMR spectroscopy. Single crystal X-ray diffraction study revealed that spiropyranocoumarin 5b self-assembled to form sheet-like arrangement. However, benzofuranyl coumarin 6 was found to display helix-like architecture in the crystalline state. Scanning electron microscopy (SEM) images of compound 5b exhibited flat fibrillar morphology, whereas compound 6 revealed formation of vesicular structure. These types of small heterocyclic molecules are decent candidates for producing promising soft materials.

Design and synthesis of novel thiazolidinone hybrid as α-amylase inhibitor, glucose uptake and antioxidant activity

A design and synthesis of novel series of substituted thiazolidinone has been synthesised from 2-amino-thiazole and pyrazole-2-aldehyde using DCC under mild condition. These compounds were first examined for α-amylase inhibition, glucose uptake activity and antioxidant activities. The α-amylase inhibition profile was found to be competitive for compound 3b. Including, compounds 3h exhibited significant glucose update activity with IC50 values of 10.21 μM. Additionally, the free-radical scavenging activity of 3a-n was assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay.

Multitargeted molecular docking and dynamics simulation of thymol-based chalcones against cancer protein markers: Synthesis, characterization, and computational study

Cancer prevention has become a significant public health concern in the 21st century, ranking as the second leading cause of global mortality following cardiovascular diseases. Despite prominent advancements in treatment, addressing cancer remains a substantial public health challenge, necessitating precise interventions tailored to diverse cancer types. The targeting of Epidermal Growth Factor Receptor (EGFR) has emerged as a fundamental strategy in modern cancer therapy due to its critical role in oncogenesis. Chalcones, a subclass of flavonoids, are promising anticancer agents due to their ability to target multiple cellular pathways implicated in cancer progression. The presence of α, β-unsaturated carbonyl moiety is a key structural feature attributed to their biological activity. This study presents an efficient synthesis approach for chalcone derivatives 4a-f designed from natural thymol. The synthesized compounds were further characterized by HRMS, 1H and 13C NMR spectral data, and further evaluated for in silico studies through molecular docking, molecular dynamic simulation, and ADMET screening. All the designed compounds 4a-f displayed favourable physicochemical properties and ADMET profiles. Molecular docking revealed favourable interactions between compounds 4a-f and the EGFR target protein. Compound 4d (p-nitro) and 4b (p-methyl) showed the more favourable docking score with low energy conformation (-8.02 kcal/mol), (-7.42 kcal/mol) respectively compared to the standard drug Gefitinib. Molecular dynamic simulations confirmed the stability of compounds 4d and 4b, exhibiting consistent structural stability in ligand-protein complexes throughout the 100 ns simulation. Acceptable RMSF values for amino acid residues indicated structural integrity and a stable protein-ligand interaction. The study identified 4d and 4b as promising leads for targeting EGFR.

Synthesis and characterization of newly phthalocyanine molecules: Their enzyme inhibition and antioxidant properties, in silico and in vitro

Pcs exhibiting maximum absorption in the phototherapeutic window continue to shine as a beacon of hope in the treatment of cancer. In particular, they maintain skin sensitivity after treatment and can treat deep-seated tumors by stimulating them with broad-spectrum radiation. This makes them advantageous compared to their counterparts. In this study, Novel 1,2,3-triazole schiff base (5a), its methoxy homolog (5b), and their silicon complexes (SiPc-6a and SiPc-6b) were synthesized. Their proposed structures were confirmed by FT-IR, NMR, UV–vis and MS instrumental techniques. Compound (6b) showed inhibitory activity on amylase and glucosidase enzymes. Moreover, considering the glucosidase activity, compound (6b) (IC50, 22.4 ± 1.0 µM) was observed to be more effective than the standard compound (IC50, 186.1 ± 5.8 µM). Molecular docking studies showed that the synthesized compounds bind to the same enzymes with high affinity. The binding energy of SiPc-6a compound with α-amylase, α-glucosidase and tyrosinase enzymes are -10.28, -11.31 and -11.9 kcal/mol, respectively. And another compound, SiPc-6b, has a binding energy of -11.46, -10.11 and -10.27 kcal/mol with a-amylase, a-glucosidase and tyrosinase enzymes, respectively. Based on experimental results that support each other with binding energy values in quality and quantity indicating efficient binding, it is concluded that these compounds can be used in candidate drug discovery. Beside these, as a result of the studies, it was understood that all molecules have antioxidant activity. Additionally, molecular electrostatic potentials, frontier orbital analysis, natural bond orbital (NBO) properties of compounds calculated with DFT and TD-DFT methods and these properties associated with structural properties.

Multifunctional anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular docking study of new 2-phenoxyacetamide/3-phenoxypropanamide/4-oxobutanamide derivatives

In the current study, three series of new compounds were designed and synthesized through hit optimization, based on the hit compound with a structure (E)-N-(4-{[benzyl(methyl)amino]methyl}thiazol-2-yl)-3-(3,4-dimethoxyphenyl)prop‑2-enamide, which was found as a potential multifunctional anti-Alzheimer agent in our previous study. Then, the biological activities of synthesized compounds (4a-c, 13a-b and 15a-c) were evaluated. The results indicated that 4b, a 2-phenoxyacetamide derivative, exhibited good multifunctional activities. Namely, compound 4b displayed better BChE inhibition (BChE IC50 = 2.10 µM) and antioxidant activity (ORAC = 1.18 Trolox equivalents) compared to the hit compound (BChE IC50 = 14.70 µM, ORAC = 0.5 Trolox equivalents). Additionally, 4b was able to chelate all tested biometals and it also exhibited a neuroprotective effect (63 %), comparable to reference ferulic acid (77 %) while maintaining its safety upon PC12 cell line. When it comes to lowering the levels of TNF-α, NO, IL-1β, and IL-6, 4b performed better activity, relative to the other synthesized compounds. Subsequently, in silico studies such as physicochemical properties, density functional theory (DFT) computational approach and molecular docking studies were performed.

Quantum chemical modelling, molecular docking, synthesis and experimental anti-microbial activity of 1,4-diazepan linked piperidine derivative

BackgroundIn this work, we represent synthesis, in silico analysis and biological activity of 1,4 diazepine linked piperidine derivatives (6a–6o). All the derivatives were screened for their anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. Compounds were synthesized from reaction of tert-butyl 1,4-diazepane-1-carboxylic, butyryl chloride and varied aromatic aldehyde, further characterized by 1H NMR and LCMS spectral techniques.ResultUsing ampicillin as a positive control, the synthetic compounds 6a–6o were tested for their in-silico study and experimental anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. According to in vitro assay compound 6a, compound 6c, compound 6d, compound 6m and compound 6I showed higher activity against all the tested strains. Molecule 6i, compound 6j, compound 6k, compound 6f has good to moderate antibacterial activity. DFT computations were used to optimize the molecular geometry at the B3LYP/6-31G (d, p) theoretical level. The corresponding energy values of molecular orbitals were visualized using optimized geometries. Moreover, Auto Dock Vina 1.2.0 is used to assess molecular docking against two target proteins, Bacillus subtilis (PDB ID: 6UF6) and Protease Vulgaris (PDB ID: 5HXW). The target molecule 6b displayed the best binding energies for both. Additionally, we calculated the ADME for each molecule (6a–6o).ConclusionAll fifteen synthesized compounds were screened for their in vitro and in silico analysis. In vitro analysis for anti-microbial activity was carried out against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria and compound 6a, compound 6c, compound 6d, compound 6m and compound 6I exhibits more potent activity towards all tested strains. Molecular docking is performed against target proteins, L-amino acid deaminase from Proteus Vulgaris and LcpA ligase from Bacillus subtilis, representing the Gram-negative bacterium and Gram-positive bacterium, respectively. Compound 6b showed the highest no. of interaction with protein according to molecular docking. With the advent of innovative techniques like ADME, we select their hit compounds early on and anticipate future pharmacokinetic and pharmacodynamic benefits and drawbacks of these promising therapeutic candidates.Graphical abstract