Preliminary anticancer evaluation of new Pd(II) complexes bearing NNO donor ligands.

In this study we presented a novel series of NNO tridentate ligands generating imino, amido and oxo donor pocket for Pd(II) coordination. All the compounds were meticulously characterized by elemental analysis and advanced spectroscopic techniques, including FTIR, proton and carbon NMR. The synthesized compounds underwent rigorous evaluation for their potential as anti-cancer agents, utilizing the aggressive breast cancer cell lines MDA-MB (ATCC) and MCF-7 as a crucial model for assessing growth inhibition in cancer cells. Remarkably, the MTT assay unveiled the robust anti-cancer activity for all palladium complexes against MDA-MB-231 and MCF-7 cells. Particularly, complex [Pd(L1)(CH3CN)] exhibited exceptional potency with an IC50 value of 25.50 ± 0.30 µM (MDA-MB-231) and 20.76 ± 0.30 µM (MCF-7), compared to respective 27.00 ± 0.80 µM and 24.10 ± 0.80 µM for cisplatin, underscoring its promising therapeutic potential. Furthermore, to elucidate the mechanistic basis for the anti-cancer effects, molecular docking studies on tyrosine kinases, an integral target in cancer research, were carried out. The outcome of these investigations further substantiated the remarkable anticancer properties inherent to these innovative compounds. This research offers a compelling perspective on the development of potent anti-cancer agents rooted in the synergy between ligands and Pd(II) complexes and presenting a promising avenue for future cancer therapy endeavors.

New organosulfur metallic compounds as potent drugs: synthesis, molecular modeling, spectral, antimicrobial, drug likeness and DFT analysis.

During the present investigation, two new sulfonamide-based Schiff base ligands, 4-{[(2-hydroxy-3-methoxyphenyl)methylidene]amino}-N-(1,3-thiazol-2-yl)benzene-1-sulfonamide (L1) and 4-{[1-(2-hydroxyphenyl)ethylidene]amino}-N-(1,3-thiazol-2-yl)benzene-1-sulfonamide (L2), have been synthesized and coordinated with the transition metals (V, Fe, Co, Ni, Cu and Zn). The ligands were characterized by their physical (color, melting point, yield and solubility), spectral (UV-Vis, FT-IR, LC-MS, 1H NMR and 13C NMR) and elemental data. The structures of the metal complexes (1)-(12) were evaluated through their physical (magnetic and conductance), spectral (UV-Vis, FT-IR and LC-MS) and elemental data. The molecular geometries of ligands and their selected metal complexes were optimized at their ground state energies by B3LYP level of density functional theory (DFT) utilizing 6-311+G (d, p) and LanL2DZ basis set. The first principle study has been discussed for the electronic properties, the molecular electrostatic possibilities as well as the quantum chemical identifiers. An obvious transition of intramolecular charge had been ascertained from the occupied to the unoccupied molecular orbitals. The UV-Vis analysis was performed through time-dependent density functional theory (TD-DFT) by CAM-B3LYP/6-311+G (d, p) function. The in vitro antimicrobial activity was studied against two fungal (Aspergillus niger and Aspergillus flavus) and four bacterial (Staphylococcus aureus, Klebsiela pneumoniae, Escherichia coli and Bacillus subtilis) species. The antioxidant activity was executed as antiradical DPPH scavenging activity (%), total iron reducing power (%) and total phenolic contents (mg GAE g-1). Additionally, enzyme inhibition activity was done against four enzymes (Protease, α-Amylase, Acetylcholinesterase and Butyrylcholinesterase). All the synthetic products exhibited significant bioactivity which were found to enhance upon chelation due to phenomenon of charge transfer from metal to ligand.

Synthesis and Investigation of the Analgesic Potential of Enantiomerically Pure Schiff Bases: A Mechanistic Approach.

Schiff bases are a class of organic compounds with azomethine moiety, exhibiting a wide range of biological potentials. In this research, six chiral Schiff bases, three 'S' series (H1−H3) and three 'R' series (H4−H6), were synthesized. The reaction was neat, which means without a solvent, and occurred at room temperature with a high product yield. The synthesized compounds were evaluated for analgesic potential in vivo at doses of 12.5 and 25 mg/kg using acetic-acid-induced writhing assay, formalin test, tail immersion and hot plate models, followed by investigating the possible involvement of opioid receptors. The compounds H2 and H3 significantly (*** p < 0.001) reduced the writhing frequency, and H3 and H5 significantly (*** p < 0.001) reduced pain in both phases of the formalin test. The compounds H2 and H5 significantly (*** p < 0.001) increased latency at 90 min in tail immersion, while H2 significantly (*** p < 0.001) increased latency at 90 min in the hot plate test. The 'S' series Schiff bases, H1−H3, were found more potent than the 'R' series compounds, H4−H6. The possible involvement of opioid receptors was also surveyed utilizing naloxone in tail immersion and hot plate models, investigating the involvement of opioid receptors. The synthesized compounds could be used as alternative analgesic agents subjected to further evaluation in other animal models to confirm the observed biological potential.

Structure-based designing and synthesis of 2-phenylchromone derivatives as potent tyrosinase inhibitors: In vitro and in silico studies.

The present study describes the discovery of novel inhibitors of mushroom tyrosinase enzyme. For that purpose, a series of varyingly substituted 2-phenylchromone analogues 1-28 were synthesized and characterized in detail by various spectroscopic techniques (UV-Vis, FTIR, 1H NMR, 13C NMR) and mass spectrometry. All the derivatives (1-28) were screened in vitro for their inhibitory potential against mushroom tyrosinase enzyme. Interestingly, all the synthetic compounds displayed good to excellent inhibitory activity with IC50 values ranging from 0.093 ± 0.003 µg/ml to 23.58 ± 0.94 µg/ml for brominated 3-hydroxy-2-phenylchromones and 0.22 ± 0.017 µg/ml to 22.22 ± 1.1 µg/ml for brominated 2-phenylchromones against tyrosinase in comparison to the standard kojic acid (IC50 = 1.79 ± 0.64 µg/ml). Remarkably, the bromine atoms attached on ring A attribute to increases the inhibitory potential of 2-phenylchromone moiety and anti-tyrosinase assay demonstrated that compound 10 (IC50 = 0.093 ± 0.003 µg/ml) was found almost nineteenfold, 11 (IC50 = 0.126 ± 0.015 µg/ml) fourteenfold and 26 (IC50 = 0.22 ± 0.017 µg/ml) about eightfold more active than the positive control. Notably, among the already literature reported tyrosinase inhibitors, these analogues have been found the most active inhibitors of mushroom tyrosinase with the lowest possible IC50 values. To design and develop novel tyrosinase inhibitors using 2-phenylchromone as a structural motif in the future, a limited structure-activity relationship was established. Moreover, in silico studies were carried out to rationalize the binding mode of interactions of all the targeted compounds (1-28) with the active site of enzymes. The experimental and theoretical results are in parallel with one another. In addition, molecular description was performed with the drug-likeness and bioactivity scores. Computational analysis predicted that few compounds are in a linear correlation with Lipinski's RO5 indicating superb drug-likeness and bioactivity score for drug targets.

Synthesis and evaluation of novel S-benzyl- and S-alkylphthalimide- oxadiazole -benzenesulfonamide hybrids as inhibitors of dengue virus protease.

Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9 µM and 15.1 µM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.

Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies.

To explore new scaffolds for the treat of Alzheimer's disease appears to be an inspiring goal. In this context, a series of varyingly substituted flavonols and 4-thioflavonols have been designed and synthesized efficiently. All the newly synthesized compounds were characterized unambiguously by common spectroscopic techniques (IR, 1H-, 13C NMR) and mass spectrometry (EI-MS). All the derivatives (1-24) were evaluated in vitro for their inhibitory potential against cholinesterase enzymes. The results exhibited that these derivatives were potent selective inhibitors of acetylcholinesterase (AChE), except the compound 11 which was selective inhibitor of butyrylcholinesterase (BChE), with varying degree of IC50 values. Remarkably, the compounds 20 and 23 have been found the most potent almost dual inhibitors of AChE and BChE amongst the series with IC50 values even less than the standard drug. The experimental results in silico were further validated by molecular docking studies in order to find their binding modes with the active pockets of AChE and BChE enzymes.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies.

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.

Synthesis, structure-activity relationship and molecular docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors.

The prime objective of this research work is to prepare readily soluble synthetic analogues of naturally occurring 3-O-flavonol glycosides and then investigate the influence of various substituents on biological properties of synthetic compounds. In this context, a series of varyingly substituted 3-O-flavonol glycosides have been designed, synthesized and characterized efficiently. The structures of synthetic molecules were unambiguously corroborated by IR, 1H, 13C NMR and ESI-MS spectroscopic techniques. The structure of compound 22 was also analyzed by X-ray diffraction analysis. All the synthetic compounds (21-30) were evaluated for in vitro inhibitory potential against cholinesterase enzymes. The results displayed that most of the derivatives were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with varying degree of IC50 values. The experimental results were further encouraged by molecular docking studies in order to explore their binding behavior with the active pocket of AChE and BChE enzymes. The experimental and theoretical results are in parallel with one another.

Synthesis, structure-activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors.

The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson's reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.

Elucidating bis-pyrimidines as new and efficient mushroom tyrosinase inhibitors: synthesis, SAR, kinetics and computational studies.

In this study, a series of novel bis-pyrimidine derivatives (1P-8P) were designed, synthesized, characterized, and investigated for their in vitro inhibitory activity against mushroom tyrosinase, an enzyme critical in melanin biosynthesis and implicated in various hyperpigmentation disorders. To the best of our knowledge, the bispyrimidine scaffold has been evaluated for the first time for its tyrosinase inhibitory activity. Their inhibitory activities were assessed, revealing inhibition with IC50 values in the micromolar range. Additionally, this series of compounds were found to inhibit tyrosinase activity in a mixed-type manner, with IC50 values ranging from 12.36 ± 1.24 to 86.67 ± 3.08 µM. To further elucidate the binding interactions, molecular docking simulations were performed, identifying key residues in the active site responsible for binding affinity. Furthermore, molecular dynamics (MD) simulations were conducted to assess the dynamic behavior, stability, and binding affinity of the most potent inhibitor, compound 6P. Quantitative Structure-Activity Relationship (QSAR) models were developed to correlate the structural features of the bis-pyrimidines with their inhibitory activity, providing insights into the structure-activity relationships (SAR) that govern their potency. The experimental and theoretical findings demonstrated excellent agreement. These findings pave the way for the development of novel bis-pyrimidine-based therapeutic agents for treating hyperpigmentation and related conditions.

Design and synthesis of 2-amino-4,6-diarylpyrimidine derivatives as potent α-glucosidase and α-amylase inhibitors: structure-activity relationship, in vitro, QSAR, molecular docking, MD simulations and drug-likeness studies.

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds 4p and 6p demonstrated the most potent dual inhibition with IC50 = 0.087 ± 0.01 µM for α-glucosidase; 0.189 ± 0.02 µM for α-amylase and IC50 = 0.095 ± 0.03 µM for α-glucosidase; 0.214 ± 0.03 µM for α-amylase, respectively as compared to the standard rutin (IC50 = 0.192 ± 0.02 µM for α-glucosidase and 0.224 ± 0.02 µM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC50 value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 0.087 ± 0.01 µM to 1.952 ± 0.26 µM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure-activity relationship (QSAR) investigations showed a strong association between 1p-15p structures and their inhibitory actions (IC50) with a correlation value (R2) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein-ligand complex, and binding affinity of the most active inhibitor 4p. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski's rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.Communicated by Ramaswamy H. Sarma.

Recent developments in the synthesis and applications of terpyridine-based metal complexes: a systematic review.

Terpyridine-based metal complexes have emerged as versatile and indispensable building blocks in the realm of modern chemistry, offering a plethora of applications spanning from materials science to catalysis and beyond. This comprehensive review article delves into the multifaceted world of terpyridine complexes, presenting an overview of their synthesis, structural diversity, and coordination chemistry principles. Focusing on their diverse functionalities, we explore their pivotal roles in catalysis, supramolecular chemistry, luminescent materials, and nanoscience. Furthermore, we highlight the burgeoning applications of terpyridine complexes in sustainable energy technologies, biomimetic systems, and medicinal chemistry, underscoring their remarkable adaptability to address pressing challenges in these fields. By elucidating the pivotal role of terpyridine complexes as versatile building blocks, this review provides valuable insights into their current state-of-the-art applications and future potential, thus inspiring continued innovation and exploration in this exciting area of research.

Exploring fluorine-substituted piperidines as potential therapeutics for diabetes mellitus and Alzheimer's diseases.

In the current study, a series of fluorine-substituted piperidine derivatives (1-8) has been synthesized and characterized by various spectroscopic techniques. In vitro and in vivo enzyme inhibitory studies were conducted to elucidate the efficacy of these compounds, shedding light on their potential therapeutic applications. To the best of our knowledge, for the first time, these heterocyclic structures have been investigated against α-glucosidase and cholinesterase enzymes. The antioxidant activity of the synthesized compounds was also assessed. Evaluation of synthesized compounds revealed notable inhibitory effects on α-glucosidase and cholinesterases. Remarkably, the target compounds (1-8) exhibited extraordinary α-glucosidase inhibitory activity as compared to the standard acarbose by several-fold. Subsequently, the potential antidiabetic effects of compounds 2, 4, 5, and 6 were validated using a STZ-induced diabetic rat model. Kinetic studies were also performed to understand the mechanism of inhibition, while structure-activity relationship analyses provided valuable insights into the structural features governing enzyme inhibition. Kinetic investigations revealed that compound 4 displayed a competitive mode of inhibition against α-glucosidase, whereas compound 2 demonstrated mixed-type behavior against AChE. To delve deeper into the binding interactions between the synthesized compounds and their respective enzyme targets, molecular docking studies were conducted. Overall, our findings highlight the promising potential of these densely substituted piperidines as multifunctional agents for the treatment of diseases associated with dysregulated glucose metabolism and cholinergic dysfunction.

Synthesis, molecular docking evaluation for LOX and COX-2 inhibition and determination of in-vivo analgesic potentials of aurone derivatives.

In the current study, seven (7) aurone derivatives (ADs) were synthesized and employed to in-vitro LOX and COX-2 assays, in-vivo models of acetic acid-induced mice writhing, formalin-induced mice paw licking and tail immersion test to evaluate their analgesic potential at the doses of 10 mg and 20 mg/kg body weight. Molecular docking was performed to know the active binding site at both LOX and COX-2 as compared to standard drugs. Among the ADs, 2-(3,4-dimethoxybenzylidene)benzofuran-3(2H)-one (WE-4)possessed optimal LOX and COX-2 inhibitory strength (IC50=0.30 µM and 0.22 µM) as compared to standard (ZileutonIC50 = 0.08 µM, CelecoxibIC50 = 0.05 µM). Similarly in various pain models compound WE-4 showed significantly (p < 0.05) highest percent analgesic potency as compared to control at a dose of 20 mg/kg i.e. 77.60 % analgesic effect in acetic acid model, 49.97 % (in Phase-1) and 70.93 % (inPhase-2) analgesic effect in formalin pain model and 74.71 % analgesic response in tail immersion model. By the administration of Naloxone, the tail flicking latencies were reversed (antagonized) in all treatments. The WE-4 (at 10 mg/kg and 20 mg/kg) was antagonized after 90 min from 11.23 ± 0.93 and 13.41 ± 1.21 to 5.30 ± 0.48 and 4.80 ± 0.61 respectively as compared to standard Tramadol (from 17.74 ± 1.33 to 3.70 ± 0.48), showing the opiodergic receptor involvement. The molecular docking study of ADs revealed that WE-4 had a higher affinity for LOX and COX-2 with docking scores of -4.324 and -5.843 respectively. As a whole, among the tested ADs, compound WE-4 demonstrated excellent analgesic effects that may have been caused by inhibiting the LOX and COX-2 pathways.

Beneficial Effects of Natural Alkaloids from Berberis glaucocarpa as Antidiabetic Agents: An In Vitro, In Silico, and In Vivo Approach.

Diabetes, also known as diabetes mellitus (DM), is a metabolic disorder characterized by an abnormal rise in blood sugar (glucose) levels brought on by a complete or partial lack of insulin secretion along with corresponding changes in the metabolism of lipids, proteins, and carbohydrates. It has been reported that medicinal plants play a pivotal role in the treatment of various ailments such as diabetes mellitus, dyslipidemia, and hypertension. The current study involved exploring the acute toxicity and in vivo antidiabetic activity of berberine (WA1), palmatine (WA2), and 8-trichloromethyl dihydroberberine (WA3) previously isolated from Berberis glaucocarpa Stapf using a streptozotocin (STZ)-induced diabetic rat model. Body weight and blood glucose level were assessed on a day interval for 4 weeks. Biochemical parameters, antioxidant enzymes, and oxidative stress markers were also determined. In an acute toxicity profile, the WA1, WA2, and WA3 were determined to be nontoxic up to 500 mg/kg (b.w). After the second and third weeks of treatment (14 and 21 days), the blood glucose levels in the WA1-, WA2-, and WA3-treated groups were significantly lower than those in the diabetic control group (476.81 ± 8.65 mg/dL, n = 8, P < 0.001). On the 21st day, there was a decrease in the blood glucose level and the results obtained were 176.33 ± 4.69, 197.21 ± 4.80, and 161.99 ± 4.75 mg/dL (n = 8, P < 0.001) for WA1, WA2, and WA3 at 12 mg/kg, respectively, as opposed to the diabetic control group (482.87 ± 7.11 mg/dL, n = 8, P < 0.001). Upon comparison with the diabetic group at the end of the study (28 days), a substantial drop in the glucose level of WA3 at 12 mg/kg (110.56 ± 4.11 mg/dL, n = 8, P < 0.001) was observed that was almost near the values of the normal control group. The treated groups (WA1, WA2, and WA3) treated with the samples displayed a significant decline in the levels of HbA1c. Treatment of the samples dramatically lowered the lipid level profile. In groups treated with samples, plasma levels of triglycerides, total cholesterol, and LDL were significantly lowered [F (5, 42) = 100.6, n = 8, P < 0.001]; these levels were also significantly decreased [F (5, 42) = 129.6 and 91.17, n = 8, P < 0.001]. In contrast to the diabetes group, all treated groups had significantly higher HDL levels [F (5, 42) = 15.46, n = 8, P < 0.001]. As a result, hypolipidemic activity was anticipated in the samples. In addition to that, the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was considerably elevated in the groups treated with the sample compared to the diabetic control group (n = 8, P < 0.001).

Tris(tetraceno)triquinacenes: synthesis and photophysical properties of threefold linearly extended tribenzotriquinacenes.

The linear extension of the rigid, C(3v)-symmetrical carbon framework of tribenzotriquinacene (TBTQ) along its three wings is reported. The key step of the extension procedure consists of a Diels-Alder reaction of three ortho-quinodimethane units generated in situ at the triquinacene core. The use of 1,4-naphthoquinone provides a facile and particularly efficient access to tris(tetraceno)-annellated triquinacenes. The steady-state photophysical properties of these new oligotetracenes bearing three mutually orthogonal chomophores are determined and analyzed by DFT calculations.

Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: in vitro, kinetic, QSAR, docking and drug-likeness studies.

Tyrosinase enzyme plays an essential role in melanin biosynthesis and enzymatic browning of fruits and vegetables. To discover potent tyrosinase inhibitors, the present studies were undertaken. In this context, synthetic aurone derivatives 26-50 were designed, synthesized, and structurally elucidated by various spectroscopic techniques including IR, UV, 1H- & 13C-NMR and mass spectrometry. The target compounds 26-50 were screened for their anti-tyrosinase inhibitory potential, and thus kinetic mechanism was analyzed by Lineweaver-Burk plots. All target compounds exhibited good to excellent IC50 values in the range of 7.12 ± 0.32 µM to 66.82 ± 2.44 µM. These synthesized aurone derivatives were found as potent tyrosinase inhibitors relative to the standard kojic acid (IC50 = 16.69 ± 2.81 µM) and the compound 39 inhibited tyrosinase non-competitively (Ki = 11.8 µM) by forming an enzyme-inhibitor complex. The binding modes of these molecules were ascribed through molecular docking studies against tyrosinase protein (PDB ID: 2Y9X). The quantitative structure-activity relationship studies displayed a good correlation between 26-50 structures and their anti-tyrosinase activity (IC50) with a correlation coefficient (R2) of 0.9926. The computational studies were coherent with experimental results and these ligands exhibited good binding values against tyrosinase and interacted with core residues of target protein. Moreover, the drug-likeness analysis also showed that some compounds have a linear correlation with Lipinski's rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.Communicated by Ramaswamy H. Sarma.

Flavonoids and related privileged scaffolds as potential urease inhibitors: a review.

Infections caused by bacteria are a significant issue on a global scale, and imperative action is required to discover novel or improved therapeutic agents. Flavonoids are a class of plant-derived compounds that have a variety of potentially useful bioactivities. These activities include immediate antimicrobial properties, synergistic effect with antimicrobials, ferocious repression of pathogenicity, anti-urease activity etc. This review summarizes current studies concerning anti-urease actions of flavonoids as well as structural-activity correlation investigations of the flavonoid core structure. It is possible that if researchers investigate the many structural changes that may be made in flavonoid rings, they'll be able to build up novel compounds that have powerful and effective anti-urease properties.

Current status of N-, O-, S-heterocycles as potential alkaline phosphatase inhibitors: a medicinal chemistry overview.

Heterocycles are a class of compounds that have been found to be potent inhibitors of alkaline phosphatase (AP), an enzyme that plays a critical role in various physiological processes such as bone metabolism, cell growth and differentiation, and has been linked to several diseases such as cancer and osteoporosis. AP is a widely distributed enzyme, and its inhibition has been considered as a therapeutic strategy for the treatment of these diseases. Heterocyclic compounds have been found to inhibit AP by binding to the active site of the enzyme, thereby inhibiting its activity. Heterocyclic compounds such as imidazoles, pyrazoles, and pyridines have been found to be potent AP inhibitors and have been studied as potential therapeutics for the treatment of cancer, osteoporosis, and other diseases. However, the development of more potent and selective inhibitors that can be used as therapeutics for the treatment of various diseases is an ongoing area of research. Additionally, the study of the mechanism of action of heterocyclic AP inhibitors is an ongoing area of research, which could lead to the identification of new targets and new therapeutic strategies. The enzyme known as AP has various physiological functions and is present in multiple tissues and organs throughout the body. This article presents an overview of the different types of AP isoforms, their distribution, and physiological roles. It also discusses the structure and mechanism of AP, including the hydrolysis of phosphate groups. Furthermore, the importance of AP as a clinical marker for liver disease, bone disorders, and cancer is emphasized, as well as its use in the diagnosis of rare inherited disorders such as hypophosphatasia. The potential therapeutic applications of AP inhibitors for different diseases are also explored. The objective of this literature review is to examine the function of alkaline phosphatase in various physiological conditions and diseases, as well as analyze the structure-activity relationships of recently reported inhibitors. The present review summarizes the structure-activity relationship (SAR) of various heterocyclic compounds as AP inhibitors. The SAR studies of these compounds have revealed that the presence of a heterocyclic ring, particularly a pyridine, pyrimidine, or pyrazole ring, in the molecule is essential for inhibitory activity. Additionally, the substitution pattern and stereochemistry of the heterocyclic ring also play a crucial role in determining the potency of the inhibitor.

Evaluation of 2,3-Dihydro-1,5-benzothiazepine Derivatives as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies.

Benzothiazepines are pharmacologically active compounds, frequently utilized as a precursor for acquiring versatile molecules with several bioactivities including anti-inflammatory, anti-human immunodeficiency virus (anti-HIV), analgesic, antitumor, antimicrobial, and antitubercular. In this study, the 2,4-diphenyl-2,3-dihydro-1,5-benzothiazepine scaffold was selected for their in vitro, docking, and druglikeness studies to evaluate their inhibitory potential against mushroom tyrosinase. All synthesized analogues, 1-14, exhibited moderate to good IC50 values ranging from 1.21 to 70.65 µM. The synthesized benzothiazepine derivatives were potent tyrosinase inhibitors, which outperformed the reference kojic acid (IC50 = 16.69 µM). The kinetic analysis revealed that compound 2 (2-(3,4-dimethoxyphenyl)-4-(p-tolyl)-2,3-dihydrobenzo[b][1,4]thiazepine) was a mixed-type tyrosinase inhibitor with a Ki value of 1.01 µM. Molecular modeling studies against tyrosinase protein (PDB ID: 2Y9X) were conducted to recognize the binding modes of these analogues. The utilization of molecular dynamic (MD) simulations enabled the assessment of the protein-ligand complex's dynamic behavior, stability, and binding affinity for the compounds. These simulations ultimately led to the identification of compound 2 as a potential inhibitor of tyrosinase. Additionally, a druglikeness study was conducted, which supported the promising potential of the new analogues as novel antityrosinase agents. The in silico studies were consistent with the in vitro results, showing that these ligands had good binding scores against tyrosinase and interacted with the core residues of the target protein. Gaussian 09 was used for the geometry optimization of all complexes.