Compound 3b Research Articles

1,3,5-triazine derivatives as potential anticancer agents against lung and breast cancer cell lines: Synthesis, biological evaluation, and structure-based drug design studies

Morpholine substituted 1,3,5-triazines have been recently recognized as potent inhibitors of PI3K-mTOR kinase signalling pathway. In this paper, we have performed synthesis and in vitro anti-cancer activity of trisubstituted 1,3,5-triazine derivatives against the A549 (Lung cancer) and MCF-7 (Breast cancer) cell lines. All synthesized analogs showed good inhibitory activity against both cell lines. Out of ten compounds, only two compounds, benzyl-4-(4-(4-(4-fluorophenyl)piperazin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Compound 6b), shows 9.61 µM anticancer activity against A549 cell line and 22.68 µM activity against MCF-7 cell lines. Similarly, benzyl-4-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Compound 6c) shows 39.70 µM anticancer activity against A549 cell line and 12.88 µM activity against MCF-7 cell lines. It shows that compound 6b is a potent inhibitor for A549 lung cancer cell line, and compound 6c shows excellent inhibitory activity for MCF-7 breast cancer cell line (9.16 µM and 12.88 µM, respectively). Both compounds (Compound 6b and Compound 6c) did not show toxicity to the non-cancerous HaCaT (Immortalized human keratinocytes) cells. Additionally, molecular descriptors of all synthesized compounds (6a-j) were calculated. After in vitro studies, the potent compounds 6b and 6c were validated using molecular docking and dynamics simulation studies and informed their binding affinities and conformational stability in the binding cavity. Structure-based drug design approach was followed for designing compounds based on potential ligand-receptor interaction. The result shows that triazine analogs serve as lead structures for generating new anti-cancer drugs.

The effect of π-extended indoleninyl-dibenzotetraaza[14]annulenes on their third-order nonlinear optical properties

Two new dibenzotetraaza[14]annulenes (DBTAAs) featuring indolenine moieties were synthesised via an acetic acid-catalysed condensation of 1,2-diaminobenzene with two diformyl indolenines in good yields. The structural identity of the compounds was confirmed by NMR (1H, 13C), FT-IR and elemental analysis. UV–visible analysis displays intense absorptions in the Soret band region with ɛ ranging from 0.32 to 1.02 × 105 M−1 cm−1 in various solvents of different polarities. The absorption spectra display a slight bathochromic shift upon replacing the indolenine (4a) with benz[e]indolenine (4b) groups on the DBTAA framework. Furthermore, the spectra exhibit solvatochromism shifts due to hydrogen-bonding interactions between the solutes and solvents. The effect of the extended π-conjugation on the electronic distributions at different energy levels was computed by Density Functional Theory (DFT) calculations. Compound 4b exhibits greater Nonlinear Optical (NLO) parameters compared to 4a due to the extended π-conjugation in the molecule. Hence, 4b could be utilised as a promising material for various NLO applications.

Synthesis and antibacterial evaluation of new naphthalimide-coumarin hybrids against multidrug-resistant S. aureus and M. tuberculosis

The rapid rise in antimicrobial resistance (AMR) has become a major threat to human health. Consequently, the constant search for new antibacterial agents that work against resistant organisms has become a global initiative. To discover new antibacterial agents with improved efficacy and activity against drug-resistant organisms, we designed and synthesized a series of new naphthalimide-coumarin hybrids and evaluated them for their antimicrobial activity against a panel of bacterial and mycobacterial strains. In the preliminary evaluation, compounds 7a, 7c, 7d, 7e, 7f, 7h, 7i, 7o, 7q, 20a and 20b exhibited potent inhibitory activity against S. aureus ATCC 29213 with MICs in the range of 0.5–32 µg/mL. Compounds 7c, 7d, 7f, 7h, 7i, 7o, 20a, and 20b also exhibited good inhibitory activity against S. epidermidis with MIC 1–16 µg/mL. All these compounds were found to be non-toxic to Vero cells (CC50 = >50) and exhibited a favorable selectivity index (SI = >12.5). Additionally, these compounds 7c, 7d, 7e, 7f, 7h, 7i, 7o, 20a and 20b have shown potent inhibition against various multidrug-resistant strains of S. aureus, including VRSA with MICs in the range of 0.5–16 µg/mL. Interestingly, compound 17b showed potent antimycobacterial activity against M. tuberculosis H37Rv with MIC 1 µg/mL and a favorable selectivity index. It also exhibited potent inhibitory activity against DR-Mtb with MIC 1 µg/mL. Topoisomerase enzyme inhibition assay was carried out to validate the mechanism of action. Furthermore, in silico studies were performed to investigate the binding mode and interactions at the active site of the target enzyme. These results highlight the potential of naphthalimide-coumarin hybrids as novel antimicrobial agents.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7–9, 11–13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (1H and 13C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure–activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

Synthesis and biological evaluation of hydantoin derivatives as potent antiplasmodial agents

Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity. Notably, compound 2c exhibited excellent inhibitory activity against the tested Pf3D7 strain, with an IC50 value of 3.97 ± 0.01 nM, three-fold better than chloroquine. Following closely, compound 3b demonstrated an IC50 value of 27.52 ± 3.37 µM against the Pf3D7 strain in vitro. Additionally, all the hydantoins derivatives tested showed inactive against human MCR-5 cells, with an IC50 value exceeding 100 μM. In summary, the hydantoin derivative 2c emerges as a promising candidate for further exploration as an antiplasmodial compound.

Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

Design, Synthesis, Antifungal Activity, and 3D-QASR of Novel Oxime Ether-Containing Coumarin Derivatives as Potential Fungicides.

Structural modification of natural products is an effective approach for improving antifungal activity and has, therefore, been used extensively in the development of new agrochemical products. In this work, a series of novel coumarin derivatives containing oxime ether structures were designed, synthesized, and evaluated for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, and compounds 4a, 4c, 5a, and 6b had EC50 values equivalent to those of commercial fungicides. Compound 6b was the most promising candidate fungicide against Rhizoctonia solani (EC50 = 0.46 μg/mL). In vivo antifungal bioassays suggested that compounds 5a and 6b could serve as novel agricultural antifungals. Furthermore, microscopy demonstrated that compound 6b induced the sprawling growth of hyphae, distorted the outline of cell walls, and reduced mitochondrial numbers. Additionally, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields were elucidated using an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The results presented here will guide the discovery of potential novel fungicides for plant disease control in agriculture.

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies.

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a-h were characterized using 1H NMR, 13C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7.34 ± 0.21 μM and 4.56 ± 0.18 μM, respectively. These results were compared to standard drugs, doxorubicin (IC50 = 12.420 ± 0.5 μM) and Hoechst 33342 (IC50 = 0.422 ± 0.02 μM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.

Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors.

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 μM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression.

Design, synthesis and mechanistic study of new dual targeting HDAC/tubulin inhibitors.

Aim: The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin. Materials & methods: The target compounds (3a-c, 4a-c and 5a-c) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). Results: Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b possessed the highest potency;however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and sixpockets and tubulin polymerization protein. Conclusion: Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.

Discovery of new N-Phenylamide Isoxazoline derivatives with high insecticidal activity and reduced honeybee toxicity

Isoxazoline is a novel structure with strong potential for controlling agricultural insect pests, but its high toxicity to honeybees limits its development in agriculture. Herein, a series of N-phenylamide isoxazoline derivatives with low honeybee toxicity were designed and synthesized using the intermediate derivatization method. Bioassay results showed that these compounds exhibited good insecticidal activity. Compounds 3b and 3f showed significant insecticidal effects against Plutella xylostella (P. xylostella) with median lethal concentrations (LC50) of 0.06 and 0.07 mg/L, respectively, comparable to that of fluralaner (LC50 = 0.02 mg/L) and exceeding that of commercial insecticide fluxametamide (LC50 = 0.52 mg/L). It is noteworthy that the acute honeybee toxicities of compounds 3b and 3f (LD50 = 1.43 and 1.63 μg/adult, respectively) were significantly reduced to 1/10 of that of fluralaner (LD50 = 0.14 μg/adult), and were adequate or lower than that of fluxametamide (LD50 = 1.14 μg/adult). Theoretical simulation using molecular docking indicates that compound 3b has similar binding modes with fluralaner and a similar optimal docking pose with fluxametamide when binding to the GABA receptor, which may contribute to its potent insecticidal activity and relatively low toxicity to honey bees. This study provides compounds 3b and 3f as potential new insecticide candidates and provides insights into the development of new isoxazoline insecticides exhibiting both high efficacy and environmental safety.

Metal-Free Synthesis of 2-Aminothiazole Functionalized Imidazo[1,2-a]pyridines as Antibacterial Agents

The present work describes the synthesis, characterization, and in silico studies of some new 2-aminothiazole functionalized imidazo[1,2-a]pyridines (1a-h). The targeted compounds were synthesized by the Hantzsch?s thiazole reaction involving the condensation reaction of a-bromomethyl ketones with 1-(3-nitroimidazo[1,2-a]pyridin-2-yl)thiourea (2). The key precursor 2 was synthesized by four steps method using 2-aminopyridine and chloroacetic acid as commercially available starting materials. The synthesized compounds 1a-1h displayed considerable activity against Gram-positive bacteria. In particular, compound 1b (R=2,4-dichloro) and 1e (R=4-carbethoxy) exhibited significant activity against Staphylococcus aureus and Bacillus subtilis in comparison to the standard antibacterial drug Ampicillin. The molecular docking and DFT studies of synthesized compounds were used to study the binding modes of these compounds. The compounds showed excellent binding energy scores (-8.3 to -9.3 kcal/mol) when interacting 1KZN protein (Escherichia coli) with compounds were examined which are in agreement with in vivo antibacterial activity.. KEYWORDS :a-Bromomethyl ketones, DFT studies, Escherichia coli, Imidazo[1,2-a]pyridines, Molecular docking.

Molecular docking and synthesis of N-alkyl-isatin-3-imino aromatic amine derivatives and their antileishmanial and cytotoxic activities.

Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects. Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions. Compounds 5c and 4d with IC50 value of 50 μΜ showed cytotoxic activity on the MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC50:59 μΜ) and 72 h (IC50: 41 μΜ) incubations. The highest docking score was -7.33 kcal/mol for compound 4d. The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations.

Design, Synthesis, and in-silico Studies of New Disubstituted Benzimidazoles: Evaluation of In-vitro Anticancer and Antimicrobial Activity

A series of thirteen new benzimidazole scaffolds 4(a-m) was synthesized by nucleophilic substitution of 2-chloro- N-(aryl)-acetamides 3(a-m) with 2-(substituted phenyl)-1H-benzo[d]imidazoles 2(a-e) in N.N-Dimethylformamide. All the synthesized compounds were tested on the MCF-7 cell line, followed by antibacterial and antifungal activity. The anticancer activity was determined using MTT assay technique, whereas the antimicrobial activity was carried out using two-fold serial dilution technique. Among all the tested compounds, compound 4b exhibited the highest anticancer and antimicrobial activity, comparable to the standard drug. Finally, the binding mode analysis of the highly active compounds was performed at the active binding sites of the co-crystallized structure of the MCF-7 cell line (PDB ID 1ZXM) and glucosamine-6-phosphate synthase (PDB ID 2VF5). In silico absorption, distribution, metabolism, and excretion studies were also carried out.. KEYWORDS :Benzimidazoles, Cytotoxicity, in silico studies, MCF-7 cell lines, MTT assay.

“PROTAC” modified dihydroquinolizinones (DHQs) that cause degradation of PAPD-5 and inhibition of hepatitis A virus and hepatitis B virus, in vitro

Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) in vitro and in vivo. In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC50 of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV in vitro, being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels. Importantly, unlike RG7834, the incubation of cells in vitro with PROTAC DHQ 12b resulted in the degradation of PAPD5, as expected for a PROTAC compound, but curiously not PAPD7. PAPD5 polypeptide degradation was prevented when a proteasome inhibitor, epoxomicin, was used, indicating that proteasome mediated proteolysis was associated with the observed activities of 12b. Taken together, these data show that 12b is the first example of a PROTAC that suppresses both HAV and HBV that is based on a small molecule warhead. The possibility that it has mechanisms that differ from its parent compound, RG7834, and has clinical value, is discussed.

Synthesis, Antimicrobial Activities and Molecular Docking Studies of New N-Acylated Derivatives of 5-(2-Phenyl-1,8-naphthyridin-3-yl)-1,3,4-oxadiazol-2-amine

Present study establishes a novel synthetic route of N-acetylated derivatives of 5-(2-phenyl-1,8-naphthyridine-3-yl)-1,3,4-oxadiazole-2-amine (6a-j), which was achieved in four steps with good yields. 2-Amino nicotinaldehyde and ethyl 3-oxo-3-phenylpropanoate on refluxing with triethylamine in ethanol undergoes Friedlander synthesis to furnish ethyl 2-phenyl-1,8-naphthyridine-3-carboxylate, which further converted into 2-phenyl-1,8-naphthyridine-3-carbohydrazide by reacting with hydrazine hydrate upon reflux, followed by cyclization with cyanogen bromide in the presence of water and 1,4-dioxane with sodium bicarbonate to afford 5-(2-phenyl-1,8-naphthyridin-3-yl)-1,3,4-oxadiazol-2-amine (5). Compound 5 was acetylated using numerous symmetrical anhydrides to synthesize novel N-acetylated derivatives (6a-j). The IR, 1H, 13C NMR and mass spectral analysis were used to characterize the structure of synthetic compounds. The synthesized compounds were evaluated for their antimicrobial efficiency against bacteria (S. aureus and E. coli) using ampicillin as a standard reference and against fungi (C. albicans) using fluconazole as a standard reference. Compound 6e exhibited good antibacterial properties while compounds 6c and 6e had shown high antifungal activity, whereas remaining compounds shown moderate to weaker antimicrobial activity. The synthesized derivatives verified their docking strength against Mtb MurB (PDB ID: 5JZX) and showed significant docking activity, however, compound 6f (-10.98 kcal/mol) and compound 6b (-10.52 kcal/mol) had a strong binding affinity compared to the other synthesized compounds.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 μM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 μM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors.

A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a-e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f-j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6k-o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99μM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity.

Supramolecular networks featuring diverse array of noncovalent interactions in crystals of hydrazinylidene-benzothiazinediones: X-ray crystallographic, DFT and biochemical analysis

The intricate role of noncovalent interactions in numerous fields including chemistry, biology, catalysis, material science, and medicinal chemistry provides a continuous impetus towards the discovery of new synthons that stabilize the supramolecular architectures. In this regard, the current work presents a series of five hydrazinylidene-benzothiazinedione derivatives encompassing a wide plethora of noncovalent interactions. Despite the configurational similarity of their hydrazinylidene-benzothiazinedione component, the five crystallographic packing arrangements of 7a–c and 9a,b are unique. The principal intermolecular interactions are CH⋯O hydrogen bonds and weak CH···π interactions (Malone Type III). Inversion dimers based on CH⋯Cl interactions form for 7b while CH⋯N and CH⋯S interactions in 9a were also observed. Furthermore, the energetic properties of the supramolecular dimers, centrosymmetric (antiparallel oriented) arrangements in 7a and 7b while parallel oriented arrangements in 9a and 9b have been examined using a combined QTAIM/NCI plot methods. The medicinal chemistry potential against urease enzyme revealed compound 9b as the lead inhibitor with strong efficacy (IC50 = 0.92 ± 0.03 µM). In vitro results were complemented with molecular docking revelations where several key interactions were observed between the potent ligand and active site amino acids. ADMET profile also described compounds 7b and 9b as the best molecules with promising druglike profile.

Synthesis and biological evaluation of 3‐hydroxypyrazoles as aquaporin 9 inhibitors

AbstractA series of 3‐hydroxypyrazole derivatives have been synthesized by a base‐promoted reaction of nitro‐substituted donor–acceptor cyclopropanes with hydrazines. The synthesized compounds have been investigated for their ability to inhibit aquaporin 9 (AQP9) in rat Leydig cells (LC‐540). The protein data bank structure for AQP9 was predicted using homology modeling; and the protein–ligand interaction for the synthesized hydroxyl pyrazole derivatives were analyzed using molecular modeling and docking studies. The results of in silico analyses showed that compound 5b had a higher binding affinity with AQP9 than other compounds. Further, in vitro studies conducted in LC‐540 cells confirmed that compound 5b effectively inhibits AQP9. Hence, compound 5b may be used as an inhibitor in enhancing our understanding of AQP9 function, and in the treatment of several diseases.