Compounds 3e Research Articles

Synthesis, Anti-Oomycete and Anti-Fungal Activities of Anhydride Derivatives of Oleanolic Acid.

Oleanolic acid is a pentacyclic triterpenoid extracted and isolated from the fruit of plants in the Ligustrum lucidum Ait. in the family Oleaceae. To discover biorational natural product-based pesticides, a series of oleanolic acid derivatives containing anhydride active skeletons were prepared by ingeniously introducing an active acyloxy group at its C-28 carboxyl position, and their structures were well characterized by 1H NMR, 13C NMR, HRMS, and m.p.. The stereochemical configuration of compound 8e was confirmed using single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete and anti-fungal agents against two serious agricultural pests, Phytophthora capsici and Fusarium graminearum we assessed. Amongst evaluated compounds, 1) Compounds 8h and 8j displayed significant anti-oomycete against P. capsici, with EC50 values of 54.73 and 65.15 mg/L, respectively. 2) The target compounds have obvious selectivity, and their anti-oomycete activity is significantly better than their anti-fungal activity. 3) Interestingly, there are significant differences in the structure-activity relationship of different substituents or the same substituent at different positions anti-oomycete and anti-fungal against P. capsici and F. graminearum, respectively. The study provides an idea for further exploring the bioactivities of 28-acyloxyoleanolic acid derivatives, and develops the application of 28-acyloxyoleanolic acid derivatives containing anhydride in agriculture.

Thiophene-Linked 1,2,4-Triazoles: Synthesis, Structural Insights and Antimicrobial and Chemotherapeutic Profiles.

The reaction of thiophene-2-carbohydrazide 1 or 5-bromothiophene-2-carbohydrazide 2 with various haloaryl isothiocyanates and subsequent cyclization by heating in aqueous sodium hydroxide yielded the corresponding 4-haloaryl-5-(thiophen-2-yl or 5-bromothiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 5a-e. The triazole derivatives 5a and 5b were reacted with different secondary amines and formaldehyde solution to yield the corresponding 2-aminomethyl-4-haloaryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 6a-e, 7a-e, 8, 9, 10a and 10b in good yields. The in vitro antimicrobial activity of compounds 5a-e, 6a-e, 7a-d, 8, 9, 10a and 10b was evaluated against a panel of standard pathogenic bacterial and fungal strains. Compounds 5a, 5b, 5e, 5f, 6a-e, 7a-d, 8, 9, 10a and 10b showed marked activity, particularly against the tested Gram-positive bacteria and the Gram-negative bacteria Escherichia coli, and all the tested compounds were almost inactive against all the tested fungal strains. In addition, compounds 5e, 6a-e, 7a-d and 10a exhibited potent anti-proliferative activity, particularly against HepG-2 and MCF-7 cancer cell lines (IC50 < 25 μM). A detailed structural insight study based on the single crystals of compounds 5a, 5b, 6a, 6d and 10a is also reported. Molecular docking studies of the highly active antibacterial compounds 5e, 6b, 6d, 7a and 7d showed a high affinity for DNA gyrase. Meanwhile, the potent anti-proliferative activity of compounds 6d, 6e and 7d may be attributed to their high affinity for cyclin-dependent kinase 2 (CDK2).

Synthesis, anticancer, α-glucosidase inhibition, molecular docking and dynamics studies of hydrazone-Schiff bases bearing polyhydroquinoline scaffold: In vitro and in silico approaches

A series of hydrazone-Schiff base derivatives of polyhydroquinoline (PHQ) nucleus have been synthesized, structurally deduced by NMR (13C- and 1H-) and HR-ESI-MS spectroscopic methods and finally subjected for anti-cancer and α-glucosidase inhibitory activities. The MTT assay's results exposed that these eight compounds (2j, 2u, 2t, 2w, 2s, 2r, 2x, and 2d) presented notable activity against breast cancer MDA-MB-231 cells having IC50 in the range of 11.4 ± 0.2 to 15.1 ± 0.4 µM, while the remaining fourteen compounds displayed significant to good anti-breast cancer activity. In case of α-glucosidase inhibition, eight compounds (2n, 2j, 2e, 2o, 2w, 2q, 2v, and 2l) exhibited superior inhibition against α-glucosidase enzyme with IC50 values ranging from 8.72 ± 0.14 to 16.16 ± 0.17 µM, compare with the standard acarbose. Additionally, the remaining eighteen derivatives showed significant to least inhibitory activity. The in silico docking, and molecular dynamic displayed the minimal divergence in MM-PBSA values for 2n, 2j, 2e, and 2o which suggests a strong and stable interaction with the protein's amino acid backbone. Pharmacokinetic profiles and anti-glucosidase ability suggested them as potential drug candidates for further studies.

Design and synthesis of new benzothiazole-piperazine derivatives and in vitro and in silico investigation of their anticancer activity

In this work, novel benzothiazole-piperazine acetamide (2a-2l) analogs were synthesized and evaluated their anticancer activity. The 1HNMR , 13CNMR and LC-MS/MS spectral data and elemental analyses were used to clarify the structure of the final molecules. The title compounds were procured by reacting 2‑chloro-N-(6-substituted benzothiazole-2-yl) acetamide with some piperazine derivatives. Cytotoxicity and apoptosis parameters including Annexin V binding capacities, effect on cell cycle, caspase-3 activation and mitochondrial membrane depolarization effect were evaluated to determine anticancer profile of the final molecules on A549 (human lung adenocarcinoma), C6 (glioma cell line) and NIH/3T3 (mouse embryoblast cell line). Mostly, the final molecules showed significant cytotoxic profile with prominent selectivity. 2c (IC50: 7.23±1.17, SI: 6.93), 2d (IC50: 17.50±4.95; SI: 11.59), and 2 h (IC50: 10.83±0.76; SI: 29.23) showed significant and selective cytotoxic activity. Compounds 2b, 2c and 2e provoked apoptosis of A549 cells with potential higher than cisplatin as determined by flow cytometry. The cell cycle analysis of 2b, 2e, 2 g, and 2 h suggested that the A549 cells were affected during G0/G1 phase. Caspase-3 activation was observed on cells by compounds 2a, 2e, 2i and 2l at most. The highest mitochondrial membrane depolarization ratios were seen treated by compounds 2e, 2 h, and 2j. None of the analogs displayed any obvious inhibition activity on MMP-9. The physicochemical properties were predicted for all compounds and also molecular docking and dynamics simulation studies were realized for compound 2e, namely N-(6-methoxybenzothiazol-2-yl)-2-(4-(p-tolyl) piperazin-1-yl) acetamide. The results indicated that merging benzothiazole and piperazine derivatives via acetamide bridge is promising in cancer research because these moieties can interact with the loop and ß-sheet regions of MMP-9. So, 2e was considered as a potential therapeutic agent against lung carcinoma.

Synthesis and characterization of new hexahydroquinoline derivatives and evaluation of their cytotoxicity, intracellular ROS production, and inhibitory effects on inflammatory mediators.

Inflammation is a response to injury and infection in an organism. It can be categorized as acute or chronic. Chronic inflammation is the underlying cause of many diseases such as Alzheimer disease, diabetes, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. Recent studies have proven the antiinflammatory properties of 1,4-dihydropyridines (1,4-DHPs) and their derivatives, which have many biological activities including the blocking of calcium channels. In this study, 15 compounds that are condensed derivatives of 1,4-DHPs, with the general structure of hexahydroquinoline-3-carboxylate, were synthesized. These compounds, expected to show inhibitory activity against inflammatory mediators, were obtained by the reaction of 4-(difluoromethoxy)benzaldehyde, substituted/nonsubstituted 1,3-cyclohexanedione derivatives, and appropriate alkyl acetoacetate compounds in the presence of ammonium acetate as a nitrogen source according to the Hantzsch synthesis method. The structures of the synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, and HRMS methods. The cytotoxic properties of the compounds were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method in the 3T3 cell line. Among the 15 compounds, the three compounds with the lowest levels of cytotoxic effects were selected for further experiments. Inflammation was induced by lipoxygenase and the effects of the selected compounds on the levels of reactive oxygen species, cytokines, and complement C3 and C9 regulatory proteins were investigated. It was found that the three selected compounds decreased the levels of transforming growth factor-beta 1 (TGF-β1). Among these compounds, compound 3e provided the most significant decrease in this cytokine. Moreover, 3e increased both C3 and C9 levels. Molecular modeling studies also showed that 3e had better affinity for TGF-β1. When the binding modes of these compounds in the active site of TGF-β1 were analyzed, it was found that compound 3e had hydrophobic interactions with amino acids Leu142, Tyr84, and Ile13; halogen bond interactions with Asp92; and hydrogen bond interactions with Ser89, Gly88, and Gly14 in the active binding site. Further in vitro and in vivo studies are needed to show the possible mechanism of action of compound 3e.

Synthesis, Biological Evaluation and Molecular Docking Studies of Benzimidazole Derivatives Substitutes as New Antimicrobial Agents

Benzimidazole derivatives have assumed an imperative moiety in the hypothetical improvement in heterocyclic science and furthermore utilized broadly in organic synthesis. The synthesis, structure and biological activities of benzimidazole derivatives have been focal point of research enthusiasm for the field of medication because of potential exercises displayed by them. Developments of more current lead atoms are utilized to improve pharmacological action and lessen drug toxicities. After extensive literature review it was thought worthwhile to synthesize some Benzimidazole derivatives and evaluate their antibacterial and antifungal activities. A series of new 2-(1&amp;lt;I&amp;gt;H&amp;lt;/I&amp;gt;-benzimidazole-2-&amp;lt;i&amp;gt;yl&amp;lt;/i&amp;gt;) phenyl)-2-(substituted benzylidene) hydrazine was designed for showing the above activity. The different hydrazine derivatives (4a-4i) were synthesized by using different substituted benzaldehyde compounds. The structures of synthesized compounds were characterized by IR, &amp;lt;sup&amp;gt;1&amp;lt;/sup&amp;gt;H NMR, Mass spectral data and elemental analysis. Synthesized compounds were tested &amp;lt;i&amp;gt;in vitro&amp;lt;/i&amp;gt; for different kinds of pharmacological activity of this class of medications including antibacterial and antifungal action. The compounds 4d and 4e found most active against &amp;lt;i&amp;gt;E.coli&amp;lt;/i&amp;gt; and &amp;lt;i&amp;gt;P. aeurigenosa &amp;lt;/i&amp;gt;and 4i found to be most active against &amp;lt;i&amp;gt;B.subtilis&amp;lt;/i&amp;gt; and &amp;lt;i&amp;gt;S.aureus.&amp;lt;/i&amp;gt; The derivative 4c shows good activity against &amp;lt;i&amp;gt;C.albicans &amp;lt;/i&amp;gt;and &amp;lt;i&amp;gt;A.niger. &amp;lt;/i&amp;gt;Molecular docking analysis was performed to investigate the binding affinity of the synthesized compounds with target proteins. By means of this research it is concluded that Benzimidazole derivatives are a potent compound compressing of different pharmacological activities and this has been proved by docking studies too. Further evaluation of their properties is required before they can be adopted for widespread use.

Exploration of green catalytic Hantzsch process for synthesis of polyhydroquinoline derivatives and their in silico & in vitro evaluation as anti-tubercular agents

Polyhydroquinolines (PHQ) were long known for various pharmacological activities and numerous methods were reported for their synthesis by using different reaction conditions and catalysts. An attempt has been made to synthesize PHQs by following the environmental friendly green chemical approaches by using reusable and recyclable catalyst and solvent materials. Twelve compounds (2A-2L) were synthesized with varied substitutions on the aromatic ring by following the Hantzsch one-pot approach with bleaching earth clay and polyethylene glycol. Use of novel reaction conditions has improved the yield and drastically reduced the time required for the completion of the reaction. The DFT analysis revealed the structural features and the stability of the compound, and later the compounds were subjected to molecular docking against two key proteins of the M. tuberculosis H37 Ra InhA and DprE1. It was found that few of the compounds showed excellent binding interactions compared to the co-crystalized ligand. Later, all the synthesized compounds were subjected to the in vitro antimycobacterial activity using the Kirby-Bauer disk diffusion method, MICs were calculated by REMA assay and the hemolytic assay was performed to check cytotoxicity. Compounds 2K and 2E were found to show better inhibitory activity than the standard rifampin. The antimycobacterial activity of the PHQ compounds might be due to the interaction of the InhA and DprE1, which can be correlated positively and supported by the structural features and the in silico interaction data. Parallelly, molecular dynamic simulation studies were carried out with ligand 2K for the time frame of 100 ns against both targets InhA and DprE1 revealing the formation of stable complexes which further validate the ligand 2K as a potential lead molecule for further studies. The compounds can be further subjected to lead optimization for improved activity.

Structure-guided Development of Novel Benzothiophene Derivatives as PLK1-PBD Inhibitors

Background: Polo-like kinase 1 (PLK1), a validated target for tumor therapy, plays a key role in mitosis and is over-expressed in many tumors. In addition to its N-terminal kinase domain, PLk1 also harbors a C-terminal polo-box domain (PBD). Objective: A candidate based on PLK1-PBD was developed as a promising compound for future development. Methods: Seventeen small molecule PLK1-PBD inhibitors were designed, synthesized and evaluated for PLK1-PBD inhibitory activities by fluorescence polarization (FP) assay. The compounds with better inhibitory activities were further assessed for their anti-proliferative activities using a CCK-8 method. Results: The inhibitory rates of compounds 7a, 7d, 14a, 14d, 14e and 14f exceeded 98%. The IC50 values of compounds 7d, 14d, 14e, and 14f were 0.73 μM, 0.67 μM, 0.89 μM and 0.26 μM, proving better than MCC1019. Compound 14f showed the best inhibitory activity (IC50: 0.26 μM) and antiproliferative activities against three cancer cell lines (HeLa, HepG2 and MG63). Especially, compound 14f also exhibited acceptable safety profiles in the human ether-a-go-go related gene (hERG) and normal cell tests. The results of docking and prediction studies indicated that compound 14f had a high binding affinity to the target, with good drug-like absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Conclusion: Compound 14f can be a promising compound for future development.

Novel benzenesulfonamides as dual VEGFR2/FGFR1 inhibitors targeting breast cancer: Design, synthesis, anticancer activity and in silico studies

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.

Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (–SeCN and –SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS-CoV-2 main protease.

The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP-1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP-1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP-1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.

Indole-core inhibitors of influenza a neuraminidase: iterative medicinal chemistry and molecular modeling

Influenza viruses that cause seasonal and pandemic flu are a permanent health threat. The surface glycoprotein, neuraminidase, is crucial for the infectivity of the virus and therefore an attractive target for flu drug discovery campaigns. We have designed and synthesized more than 40 3-indolinone derivatives. We mainly investigated the role of substituents at the 2 position of the core as well as the introduction of substituents or a nitrogen atom in the fused phenyl ring of the core for inhibition of influenza virus neuraminidase activity and replication in vitro and in vivo. After evaluating the compounds for their ability to inhibit the viral neuraminidase, six potent inhibitors 3c, 3e, 7c, 12o, 12v, 18d were progressed to evaluate for cytotoxicity and inhibition of influenza virus A/PR/8/34 replication in in MDCK cells. Two hit compounds 3e and 12o were tested in an animal model of influenza virus infection. Molecular mechanism of the 3-indolinone derivatives interactions with the neuraminidase was revealed in molecular dynamic simulations. Proposed inhibitors bind to the 430-cavity that is different from the conventional binding site of commercial compounds. The most promising 3-indolinone inhibitors demonstrate stronger interactions with the neuraminidase in molecular models that supports proposed binding site.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

Multicomponent reaction for the synthesis of novel nicotinonitrile analogues bearing imidazole or triazole moieties: Synthesis, antioxidant activity, molecular docking, and ADMET studies

The study is aimed to synthesize, characterize and evaluate antioxidant activity of novel highly functionalized nicotinonitrile analogues bearing imidazole or triazole moieties. The targeted compounds were synthesized via one-pot four component reaction and characterized by elemental and spectrometric analyses. The newly 16-synthesized compounds were assessed as antioxidant agents using the total antioxidant capacity assay. The experimental results indicated that four out of sixteen compounds exhibited the most antioxidant effect with 38.81 and 18.66 mg AAE/g considering ascorbic acid equivalent. The molecular docking screening on the novel potential compounds, further supported by ADMET/drug-likeness screening was conducted. The outcomes of the docking simulations revealed that compounds 4e, 4f, 4g, and 6h are considered safe and non-toxic. These 4 compounds exhibited significant affinity, as evidenced by binding energies of -11.9, -10.9, -11.2, and -11.60 kcal/mol, respectively, with the active site of human cytochrome P450. Additionally, these compounds showed significant binding energies with NAD(P)H Oxidase of -9.90, -9.50, -9.90, and -9.50 kcal/mol, respectively. These interactions involved diverse types of molecular interactions and demonstrated favorable binding energies, indicating the potential of these compounds to modulate antioxidant enzymes and demonstrate promising antioxidant effects. The in-silico ADMET profiles of compounds 4e, 4f, 4g, and 6h indicated their adherence to the Lipinski rules, subsequently, they could be potential orally bioavailable drug-like molecules.

Synthesis, Characterization, and Evaluation of Antioxidant Activities of 2-(1-(Substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines

Background: Pyrimidine and hydrazones are well known for their therapeutic applications. Objective: To investigate the antioxidant activities of compounds having pyrimidine and hydrazone motifs in hope of finding molecules with robust antioxidant activities. Methods: Hydrazones were obtained by condensing pyrimidine hydrazine with aromatic ketones. The structures of these compounds were established on the basis of NMR, FTIR and mass spectral data analysis. Results: All compounds were assessed for their antioxidant potential against DPPH, hydrogen peroxide, nitric oxide and superoxide free radicals. Conclusion: A series of twelve 2-(1-(substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines was synthesized and compounds 6d, 6e, 6h, and 6j found to have good antioxidant activities.

Synthesis and in-silico Studies of 4-phenyl thiazol-2-amine Derivatives as Putative Anti-breast Cancer Agents.

Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored. Synthesis and in-silico</i> studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds' capacity to bind ER-α protein target. In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted. Most of the synthesized compounds have shown dock scores ranging from -6.658 to - 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein's active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds' ADME properties are below acceptable limits. Compound 3e showed the best docking score of -8.911. All compounds' ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro</i> and in-vivo</i> in the future.

Design, Synthesis, Anti-Cancer, Anti-inflammatory and In Silico Studies of 3-Substituted-2-Oxindole Derivatives.

This study focuses on the design and synthesis of 3-substituted-2-oxindole derivatives aimed at developing dual-active molecules with anti-cancer and anti-inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug-likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI50 value 3.00E-05 against MDA-MB-231, 4 b has shown GI50 value 2E-05 against MDA-MB-231, 4 c has shown GI50 value 6E-05 against VERO, 4 d has shown GI50 value 8E-05 each against both the MDA-MB-231 and MCF-7 and 4 e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (63.04 %) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4 d, 4 e, 3 b, 3 i, and 3 e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The Quantum Mechanics-based Independent Gradient Model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.

Probing N-substituted 4-(5-mercapto-4-ethyl-4H-1,2,4-triazol-3-yl)-N-phenylpiperdine-1-carboxamides as potent 15-LOX inhibitors supported with ADME, DFT calculations and molecular docking studies

In our continuous efforts to find out leads against the enzyme 15-lipoxygenase (15-LOX), the current study deals with the synthesis of a series of new N-alkyl/aralkyl/aryl derivatives of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)methylacetamide (7a-n) with anti-LOX activities. The synthesis was started by reacting phenylisocyanate with isonipecotate that sequentially converted into N-substituted ester (1), hydrazide (2), semicarbazide (3) and N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The final compounds, 7a-n, were obtained by reacting 4 with various N-alkyl/aralkyl/aryl electrophiles. Both the intermediates and target compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX by chemiluminescence method. The eight compounds 7e, 7j, 7h, 7a, 7g, 7b, 7n, 7c showed potent inhibitory activities against 15-LOX with values ranging from IC50 0.36 ± 0.15 μM (7e) to IC50 6.75 ± 0.17 μM (7c) compared with the reference quercetin (IC50 4.86 ± 0.14 μM) and baicalein (IC50 2.24 ± 0.13 μM). Two analogues (7l, 7f) had significantly outstanding inhibitory potential with IC50 values 12.15 ± 0.23 μM and 15.54 ± 0.26 μM, whereas, the derivatives 7i, and 7d displayed IC50 values of 21.56 ± 0.27 μM, 23.59 ± 0.24 μM and the compounds 7k, 7m were found inactive. All analogues exhibited blood mononuclear cells (MNCs) viability >75 % at 0.25 mM concentration as determined by MTT method. Calculated pharmacokinetic properties projected good lipophilicity, bioavailability and drug-likeness properties and did not violate Lipinski's/Veber rule. Molecular docking studies revealed lower binding free energies of all the derivatives than the reference compounds. The binding free energies were −9.8 kcal/mol, −9.70 k/mol and −9.20 kcal/mol for 7j, 7h and 7e, respectively, compared with the standard quercetin (−8.47 kcal/mol) and baicalein (−8.98 kcal/mol). The docked ligands formed hydrogen bonds with the amino acid residues Gln598 (7e), Arg260, Val 126 (7h), Gln762, Gln574, Thr443, Arg580 (7j) while other hydrophobic interactions observed therein further stabilized the complexes. The results of density functional theory (DFT) revealed that analogues with more stabilized lower unoccupied molecular orbital (LUMO) had significant enzyme inhibitory activity. The data collectively supports these molecules as leads against 15-LOX and demand further investigations as anti-inflammatory agents.

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Synthesis of indole-functionalized isoniazid conjugates with potent antimycobacterial and antioxidant efficacy.

Aim: Developing potent medicinal alternates for tuberculosis (TB) is highly desirable due to the advent of drug-resistant lethal TB strains.Methods & results: Novel indole-isoniazid integrates have been synthesized with promising antimycobacterial action against the H37Rv strain, and the nitro analogs 4e and 4j show the highest efficacy with a minimum inhibitory concentration of 1.25μg/ml. The molecular docking studies against InhA support the experimental findings. Indole conjugates display remarkable radical quenching efficiency, and compounds 4e and 4j demonstrate maximum IC50 values of 50.19 and 52.45μg/ml, respectively. Pharmacokinetic analysis anticipated appreciable druggability for the title compounds.Conclusion: The notable bioaction of the indole-isoniazid templates projects them as potential lead in developing anti-TB medications with synergetic antioxidant action.