Analogues 1a Research Articles

Design, Synthesis, and Evaluation of Piperazine‐7‐Deazapurine Based Thiazolidone Derivatives as Novel ROCK Inhibitors

AbstractIn this research journey of exploring ROCK inhibitors, we synthesized a new series of substituted piperazine‐7‐deazapurine‐linked thiazolidone analogs (10a–s) via a five‐step process, and employing sophisticated molecular modeling techniques, optimized the crystal structures of ROCK1 and ROCK2 to evaluate the binding affinities of these compounds. The evaluation of ROCK inhibitory activity demonstrated generally low binding affinities across the series, as reflected in their pIC50 values. Significantly, compound 10h emerged as a potent inhibitor of ROCK1 with an impressive pIC50 value of 6.54. Similarly, compound 10q showed strong inhibitory effects on ROCK2, marked by a pIC50 value of 6.03. Notably compound 10k exhibited a balanced inhibitory on both ROCK isoforms with a pIC50 of 5.24 and 5.31 against ROCK1 and ROCK2 respectively, suggesting its viability for further exploration. This research provides significant insights into the structure activity relationships (SAR) of kinase inhibitors, paving the way for designing more targeted and efficacious therapeutic options for diseases involving ROCK kinases.

6-aryloxy-2-aminopyrimidine-benzonitrile hybrids as anti-infective agents: Synthesis, bioevaluation, and molecular docking.

This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets. Notably, compounds 5p (2,4-dimethyl substitution; IC50 = 44 ± 4.9 µM; selectivity index [SI] = 20) and 5 s (3-thiophenphenyl; IC50 = 6 ± 1 µM; SI = 120) showed significant antiviral activity against pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with positive toxicity profiles and also exhibited good IC50 values (5p, IC50 = 10 ± 2 µM; SI = 9 and 5 s, IC50 = 16 ± 2 µM; SI = 60) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Wuhan strain) compared with favipiravir. In addition, analogs 5a, 5r, 5t, and 5u showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain and compounds 3, 5f, 5n, and 5q showed moderate antibacterial activity against gram+ve and gram-ve bacterial strains, suggesting that this scaffold has a broad spectrum of therapeutic effects.

Design, Synthesis, Molecular Docking and Hypoglycemic Activity of Novel Coumarin Analogues

AbstractDiabetes and its associated conditions are significant causes of morbidity and mortality. Despite the abundance of available medications for diabetes treatment, their limitations have spurred ongoing research in this field. Consequently, there is a need to discover a potential therapeutic molecule for managing diabetes and its complications. In current research work a series of novel coumarin analogs (5a–5e) were designed, synthesized, characterized through FTIR, 1H NMR, 13C NMR, and mass spectroscopy and evaluated for antidiabetic property. Molecular docking study was performed to link its binding affinity toward AMPK. DPPH scavenging assay was performed for in vitro antioxidant activity, for reference standard ascorbic acid was taken. In vivo hypoglycemic activity was performed on streptozotocin and nicotinic acid induced diabetic rats. All synthesized molecule showed good docking, score among them compound 5b has lowest docking score −11.25 kcal/mol. Molecule 5b and 5c showed greater antioxidant potential with good IC50 value, i.e., 20.4 g/mL and 21.6 g/mL. In vivo antidiabetic study showed good control on blood glucose level, cholesterol, triglyceride, Hb1AC as well as SGOT and SGPT level on animals fed 5b when compared to metformin. This result showed that test molecule 5b has potential to lower the blood glucose level without causing any toxicity.

Isolation of Natural Veratrylidenehydrazide Compound from Wedelia Biflora and Synthesis of Veratrylidenehydrazide Analogue: Investigation of Larvicidal Activity Against Culex Quinquefasciatus and Toxicity Analysis in Nontarget Aquatic Species

AbstractIn this study, veratrylidenehydrazide was isolated from Wedelia biflora, and compounds (1a, 2a, and 3a–j) were synthesised to evaluate their larvicidal and antifeedant activities. Veratrylidenehydrazide 1a was verified using GC‐MS. The veratrylidenehydrazide analogues 2a and 3a–j were synthesised via a condensation method with yield range 71%–92%. The compounds (1a, 2a, and 3a–j) were synthesised and characterised through FT–IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. Veratrylidenehydrazide 1a was verified using GC‐MS analysis. Natural veratrylidenehydrazide compound 1a and the synthesised veratrylidenehydrazide analogues (2a, 3a–j) were screened for larvicidal activity against Culex quinquefasciatus. The larvicidal activity of compound 3g was found to be highly active, while low toxicity was observed against Oreochromis mossambicus nontarget aquatic species compared to natural veratrylidenehydrazide. Compound 3g exhibited a higher binding affinity (−8.8 kcal/mol) compared to standard of temephos (−4.5 kcal/mol), equipotential binding affinity against permethrin (−9.1 kcal/mol), and diflubenzuron (−8.5 kcal/mol). Lead molecules have larvicidal properties, and their use as insecticides makes them important.

Transition metal complexes of benzimidazole-based ligands: Synthesis, characterization, biological, and catecholase activities

Heterocyclic ligands 5a and 5b and their metal complexes (1–10) and (11–20) respectively, were synthesized and characterized by mass spectrometry, FT-IR, ESR, 1H, 13C NMR and UV–visible spectroscopy. In vitro antifungal activity of the heterocyclic analogs 5a, 5b and metal complexes (1–20) was evaluated against the fungal strains: Candida albicans, Candida glabrata, and Candida tropicalis., The results showed that Fe(III) 2 and Co(II) complex 13 display considerable antifungal activity with MIC values of 350, 375 and 435 μg/mL and 450, 455, and 455 μg/mL against C. albicans, C. glabrata, and C. tropicalis, respectively. Promising 5a, 5b, Fe(III) 2, and Co(II) complex 13 show groove binding mode with Ct-DNA, which has been confirmed by several techniques, including UV–visible, fluorescence spectroscopy, and cyclic voltammetry. PDB ID: 1BNA was used for the molecular docking investigation of the heterocyclic analogs 5a and 5b. The active Fe(III) complex 2 and Co(II) complex 13 are effectively catalyzed for the oxidation of catechol in acetonitrile to its corresponding quinone with turnover number 5.44 × 104 and 9.78 × 104 h−1, respectively with first order that follow Michaelis-Menten enzymatic kinetics. The pharmacokinetics properties of the all compounds showed good oral bioavailability. Antioxidant potential of ligands 5a, 5b, Fe(III) 2 and Co(II) complex 13 was further approximated through DPPH free radical and H2O2 with remarkable antioxidant activity.

Benzo-Crown-Ether Functionalized O-BODIPY Probes for Cations - A Selective Fluorescent Probe for Ba2.

Herein, we report the synthesis and sensing characteristics of 4,4'-methoxy-substituted BODIPY fluorescent probes (O-BODIPYs) 3, 4 and 5 equipped with differently sized benzo-crown ethers (cf. Scheme 1, 3 (benzo-15-crown-5), 4 (benzo-18-crown-6) and 5 (benzo-21-crown7)). O-BODIPYs 3, 4 and 5 exhibited in comparison to their known F-BODIPY analogues 3a, 4a and 5a (cf. Scheme 1) an improved solubility in aqueous medium and higher fluorescence quantum yields. Fluorometric study in aqueous solutions of 3, 4 and 5 in the presence of different cations show cation induced fluorescence enhancements (FE). Compared to the benzo-crown ether substituted F-BODIPY analogues 3a, 4a and 5a, we found for the free O-BODIPYs 3, 4 and 5 higher fluorescence quantum yields (φf) but lower cation induced FEs. We show that in aqueous medium the fluorescence quenching process (OFF switching), a photoinduced electron transfer, in O-BODIPYs 3, 4 and 5 is less effective and consequently sensitive and selective ON switching of the fluorescence by cations, too. Albeit these observations the novel benzo-21-crown-7 equipped fluorescent probe 5 exhibits a good fluorometric Ba2+ selectivity and Ba2+ sensitivity in conjunction to their aqueous solubility.

Antiproliferative, apoptotic and anti-inflammatory potential of 5H-benzo[h]thiazolo[2,3-b]quinazoline analogues: Novel series of anticancer compounds

Lung cancer (LC) is the most common cancer in males. As per GLOBOCAN 2020, 8.1 % of deaths and 5.9 % of cases of LC were reported in India. Our laboratory has previously reported the significant anticancer potential of 5H-benzo[h]thiazolo[2,3-b]quinazoline analogues. In this study, we have explored the anticancer potential of 7A {4-(6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)phenol} and 9A {7-(4-chlorophenyl)-9-methyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline}by using in-vitro and in-vivo models of LC. In this study, we investigated the antiproliferative potential of quinazoline analogues using A549 cell line to identify the best compound of the series. The in-vitro and molecular docking studies revealed 7A and 9A compounds as potential analogues. We also performed acute toxicity study to determine the dose. After that, in-vivo studies using urethane-induced LC in male albino Wistar rats carried out further physiological, biochemical, and morphological evaluation (SEM and H&E) of the lung tissue. We have also evaluated the antioxidant level, inflammatory, and apoptotic marker expressions. 7A and 9A did not demonstrate any signs of acute toxicity. Animals treated with urethane showed a significant upregulation of oxidative stress. However, treatment with 7A and 9A restored antioxidant markers near-normal levels. SEM and H&E staining of the lung tissue demonstrated recovered architecture after treatment with 7A and 9A. Both analogues significantly restore inflammatory markers to normal level and upregulate the intrinsic apoptosis protein expression in the lung tissue. These experimental findings demonstrated the antiproliferative potential of the synthetic analogues 7A and 9A, potentially due to their anti-inflammatory and apoptotic properties.

Effects of natural Ionones and derived novel analogues with simplified structures on behavioral responses of whiteflies.

Whiteflies are major pests in agriculture, causing damage to crops and transmitting plant viruses. Using Volatile Organic Compounds (VOCs) as semiochemicals offers a sustainable approach for combating whiteflies. One such group of compounds, represented by β-ionone, has been found to possess repellent/attractant properties. To further explore the behavioral effects of these compounds on whiteflies, we selected five natural ionone compounds and synthesized six novel analogues to examine the impact of structural variations on whitefly behavior. Our results demonstrated that β-ionone and its analogues have a significant impact on the behavior of whiteflies. Among them, 0.01% pseudo ionone solution exhibited an attractant effect on whiteflies. Notably, the application of 1% β-ionone and 0.1% β-ionol solution demonstrated a notable repellent effect and oviposition deterrent effect on whitefly. We also found that the novel ionone analogue (±)1A exhibited a strong repellent effect. Both β-ionol and compound (±)1A possess high logP values and low saturation vapor pressures, which contribute to enhanced lipophilicity, making them more likely to penetrate insect antennae and prolong their presence in the air. The newly discovered ionone analogue (±)1A and β-ionol exhibit improved repellent effects, while pseudo ionone shows an attractant effect. These three compounds hold promising potential for development as novel biological control agents. Our work highlights the efficacy of VOCs as a protection method against whiteflies. These findings indicate that our new technology for a 'push-pull' control method of B. tabaci can offer a novel tool for integrated pest management (IPM). © 2024 Society of Chemical Industry.

Design and synthesis of 4-amino-2′,4′-dihydroxyindanone derivatives as potent inhibitors of tyrosinase and melanin biosynthesis in human melanoma cells

Melanogenesis inhibition constitutes a privileged therapeutic solution to treat skin hyperpigmentation, a major dermatological concern associated with the overproduction of melanin by human tyrosinase (hsTYR). Despite the existence of many well-known TYR (tyrosinase) inhibitors commercialized in skin formulations, their hsTYR-inhibition efficacy remains poor since most of them were investigated over mushroom tyrosinase (abTYR), a model with low homology relative to hsTYR. Considering the need for new potent hsTYR inhibitors, we designed and synthesized a series of indanones starting from 4-hydroxy compound 1a, one of the two most active derivatives reported to date against the human enzyme, together with marketed thiamidol. We observed that analogues featuring 4-amino and 4-amido-2′,4′-dihydroxyindanone motifs showed two-to ten-fold increase in activity over human melanoma MNT-1 cell lysates, and a ten-fold improvement in a 4-days whole-cell experiment, compared to parent analogue 1a. Molecular docking investigation was performed for the most promising 4-amido derivatives and suggested a plausible interaction pattern with the second coordination sphere of hsTYR, notably through hydrogen bonding with Glu203, confirming their impact in the binding mode with hsTYR active site.

Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists

The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2–4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1−8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).

Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors

A series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 µM. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson’s r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity. Communicated by Ramaswamy H. Sarma

Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells

Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a–l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 µM, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of −7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and π–π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK. Communicated by Ramaswamy H. Sarma

Synthesis of some new 2-(substituted-phenyl)imidazo[4,5-c] and [4,5-b]pyridine derivatives and their antimicrobial activities.

The synthesis of 5H-imidazo[4,5-c]pyridines analogues (1a - 1h) and 4H-imidazo[4,5-b]pyridines (3a - 3c) was achieved by reacting 3,4-diaminopyridine or 2,3-diaminopyridine with Na2S2O5 adduct of corresponding benzaldehydes (a1 - a8). Alkylation of compounds (1a - 1h) and (3a - 3c) using 4-chlorobenzyl and /or butyl bromide under basic conditions (K2CO3, DMF) predominantly resulted in the formation of N5 regioisomers (2a - 2l) and N4,3 regioisomers (4a - 4c1,2), respectively. The N5,4,3-regioisomeric structures were confirmed using 2D-NOESY (Nuclear Overhauser Effect Spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation) spectra. The antibacterial and antifungal activities of the synthesized compounds (2a - 2g, 4a - 5d) were evaluated in vitro against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin resistant S. aureus, Enterococcus faecalis and Candida albicans, Candida parapsilosis. Among the synthesized compounds, promising activities were observed with compounds 2g, 2h, 4a and 4b with lowest MIC values (4-8µg/mL). The compounds 2i, 2j, 2k, 2l showed moderate activity. Additionally, a computational approach (ADMETlab 2.0) was used to evaluate the drug likeness properties of the compounds.

Synthesis of 1-(4-(dimethylamino)phenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione analogues and their anti-inflammatory activities in lipopolysaccharide-induced BV2 cells

A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC50 = 7.1 μM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC50 > 50 μM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases.

Synthesis, spectral characterization of pyrazole derived Schiff base analogs: molecular dynamic simulation, antibacterial and DNA binding studies

We have synthesized the pyrazole-bearing Schiff base derivatives (5a–5e) and (6a–6h) then the structural confirmation was supported by various spectral analyses. The antibacterial activity of all analogs was screened against bacterial strains Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Klebsiella pneumonieae and Pseudomonas aeruginosa. In comparison to the reference drug ciprofloxacin, the lead analogs 5c and 6c showed potent activity, with MIC values of 64 µg/mL against E. coli and B. subtilis. Compound 5c showed a moderate effect with a MIC value of 128 µg/mL against B. subtilis, P. aeruginosa and K. pneumonieae, while compound 6c was against E. coli and P. aeruginosa. Furthermore, the compounds 5c and 6c displayed groove binding mode towards CT-DNA by absorption, emission, competitive fluorescence studies using EtBr, CD and time-resolved fluorescence studies. Thermodynamic parameters of analogs 5c and 6c with CT-DNA were also calculated at 298, 303 and 308K temperatures by UV–visible spectroscopy. The molecular docking studies give the docking score for all compounds with PDB codes: 1BNA and 2XCT. The MD simulation study of analogs 5c and 6c was also carried out. The pharmacokinetic and ADME properties were calculated for all of the synthesized analogs (5a–5e) and (6a–6h).Communicated by Ramaswamy H. Sarma

Phenylpropanoids and a diarylpentanol from Stellera chamaejasme with acetylcholinesterase inhibitory activity

The chemical investigation on the roots of Stellera chamaejasme led to the identification of five undescribed compounds, including three lignans (1, 2, and 3b), one coumarin (4), one diarylpentanoid (5), and eight known analogues (3a, 6–10, and 11a/11b). Among them, two pairs of enantiomers were separated by chiral resolution. The structures of all compounds were elucidated by NMR spectroscopy and HRESIMS data analyses, quantum chemical calculations of NMR chemical shifts and ECD, as well as single-crystal X-ray diffraction analyses. All isolates were tested for their inhibitory activities against AChE, and compound 2 showed the most potent inhibitory activity, with an inhibition rate of 88.0% at 100 μM. In addition, the possible interaction mechanism of 2 against AChE was predicted by molecular docking.

A novel 4'-brominated derivative of fisetin induces cell cycle arrest and apoptosis and inhibits EGFR/ERK1/2/STAT3 pathways in non-small-cell lung cancer without any adverse effects in mice.

The therapeutic toxicity and resistance to currently available treatment options are major clinical challenges for the management of lung cancer. As a novel strategy, we synthesized analogues of a known flavonol, fisetin, which has shown anti-tumorigenic potential against cancer in cell culture with no adverse effects in animal models. We studied the synthetic analogues of fisetin for their anti-cancer potential against lung cancer cells, toxicity in mice and efficacy in a xenograft model. Brominated fisetin analogues were screened for their effects on the viability of A549 and H1299 lung cancer cells, and three analogues (3a, 3b, 3c), showed improved activity compared to fisetin. These analogues were more effective in restricting lung cancer cell proliferation, inducing G2 M phase cell cycle arrest and apoptosis. The fisetin analogues also downregulated EGFR/ERK1/2/STAT3 pathways. Fisetin analogue-induced apoptosis was accompanied by a higher Bax to Bcl-2 expression ratio. Based on the in vitro studies, the most effective fisetin analogue 3b was evaluated for in vivo toxicity, wherein it did not show any hepatotoxicity or adverse health effects in mice. Furthermore, analogue 3b showed greater antitumor efficacy (p < .001) as compared to its parent compound fisetin in a human lung cancer cell xenograft study in athymic mice. Together, our data suggest that the novel fisetin analogue 3b is more effective in restricting lung cancer cell growth, both in vitro as well as in vivo, without any apparent toxicity, supporting its further development as a novel anti-lung cancer agent.

Structurally diverse lignans from Solanum lyratum: chemical evidence for their acetylcholinease inhibitory activity

A chemical investigation of Solanum lyratum Thumb. (Solanace) afforded two new lignans (1b and 3) and eleven known lignan analogues (1a, 2a/2b and 4–11). Compounds 1a/1b and 2a/2b were separated as two pairs of enantiomers by chiral high-performance liquid chromatography (HPLC). Their structures were elucidated by detailed spectroscopic and comparative literature data analysis. The absolute configurations of compounds 1a/1b and 2a/2b were determined by comparing the experimental ECD data with the calculated values. All compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Notably, compared to the positive control, compounds 4 and 9 showed obvious AChE inhibition with their IC50 values of 1.30 ± 0.25 and 0.89 ± 0.04 μM, respectively. In addition, the possible interaction between acetylcholinesterase and the active compounds was also investigated by molecular docking.

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues.

With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin's promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a-c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a-c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs &gt; 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a &gt; 3b &gt; 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b &gt; 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a-c demonstrated significant binding affinity (-6.003 to -7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3.

The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.