Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as sirtuin 1 inhibitors with antiproliferative effects on cancer cells.

Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to confirm their structures. The benzoylbenzofuran and isoflavone analogues were evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and benzoylbenzofuran derivatives exhibited potent antiproliferative effects against the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated SIRT1 activity to below 50%. The most active compounds were the isoflavone quinones 38, 39, and 40, at IC50 values of 5.58 ± 0.373, 1.62 ± 0.0720, and 7.24 ± 0.823 µM, respectively. Importantly, the most active compound, 6-methoxy-4',6'-dimethylisoflavone-2',5'-quinone (39) displayed SIRT1 inhibitory activity comparable to that of the reference compound, suramin. The in silico docking simulations in the active site of SIRT1 further substantiated the experimental results and explored the binding orientations of potent compounds in the active site of the target.

Synthesis, antimicrobial evaluation, and in silico studies of quinoline-1H-1,2,3-triazole molecular hybrids.

Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline-1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39 µM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36 µM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency.

Synthesis, Cytotoxicity and Antimicrobial Evaluation of New Coumarin-Tagged ß-Lactam Triazole Hybrid.

A series of coumarin-tagged ß-lactam triazole hybrids (10a-10o) were synthesized and tested for their cytotoxic activity against MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK-293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF-7 cancer cell lines with IC50 values of 53.55 and 58.62 µm, respectively. More importantly, compounds 10b and 10d were non-cytotoxic against HEK-293 cell lines. Structure-activity relationship (SAR) studies suggested that the nitro and chloro group at the C-3 position of phenyl ring are favorable for anticancer activity, particularly against MCF-7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.

Synthesis,Antidiabetic and Antitubercular Evaluation of Quinoline-pyrazolopyrimidine hybrids and Quinoline-4-Arylamines.

Two libraries of quinoline-based hybrids 1-(7-chloroquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 7-chloro-N-phenylquinolin-4-amine were synthesized and evaluated for their α-glucosidase inhibitory and antioxidant properties. Compounds with 4-methylpiperidine and para-trifluoromethoxy groups, respectively, showed the most promising α-glucosidase inhibition activity with IC50 =46.70 and 40.84 µM, compared to the reference inhibitor, acarbose (IC50 =51.73 µM). Structure-activity relationship analysis suggested that the cyclic secondary amine pendants and para-phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N-methylpiperazine and N-ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50 =0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50 =0.05 mM), while the best DPPH scavenger is NO2 -substituted compound (IC50 =0.08 mM). Also, compound with N-(2-hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50 =0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4-amino units as crucial pharmacophores furnishing α-glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α-glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti-tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7-chloro-N-phenylquinolin-4-amine hybrid showed sub-10 µM whole-cell activities against Mycobacterium tuberculosis.

Thiazolidinone-Heterocycle Frameworks: A Concise Review of Their Pharmacological Significance.

Molecular hybridization is deemed an optimistic approach in drug design and the discovery of novel biologically active molecules as it may advance their affinity and potency while concurrently decreasing associated resistance and side effects. Approximately 20 % of approved drugs were developed using this approach in the past few years. Thiazolidinone is one of the privileged pharmacophores in medicinal chemistry and is associated with various biological activities; it forms a functional unit in several FDA-approved drugs. Consequently, this pharmacophore has attracted the attention of many research groups to further explore its pharmacological relevance by coupling it with other pharmacophoric moieties. This review presents a concise account of scholarly research exploits directed at the biological activities of newly synthesized thiazolidinone-tagged molecular hybrids. Focused attention is given to the existing structural activity relationship in each compound library and the toxicity profile of potent compounds including in silico docking studies (where applicable). This work would provide a base on which new pharmaceuticals with improved potency can be modelled.

α-Glucosidase and α-Amylase Inhibitory Potentials of Quinoline-1,3,4-oxadiazole Conjugates Bearing 1,2,3-Triazole with Antioxidant Activity, Kinetic Studies, and Computational Validation.

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4a-t and 12a-t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC50 = 15.85 µM) relative to reference drug acarbose (IC50 = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC50 = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein-ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management.

Synthesis, Anti-Plasmodial Activities, and Mechanistic Insights of 4-Aminoquinoline-Triazolopyrimidine Hybrids.

In the search of new antiplasmodial agents, a multitargeted approach was used in the synthesis of triazolopyrimidine- and 4-aminoquinolines-based hybrids. In vitro antiplasmodial evaluation on chloroquine-sensitive (3D7) and -resistant (W2) P. falciparum strains identified triazolopyrimidine-4-aminoquinoline hybrids to be the most potent in the series, outperforming bis-triazolopyrimidines. The active compounds were subjected to mechanistic studies with the plausible and expected targets including heme, PfCRT, and PfDHODH, that eventually validated the biological data. The active compound surpassed the antimalarial drug CQ by inhibiting the parasite's cellular process (hemozoin formation) and parasitic enzymes (PfCRT and PfDHODH), as confirmed by UV-vis and molecular modeling studies.

Synthesis of 1H-1,2,3-Triazole-Linked Quinoline-Isatin Molecular Hybrids as Anti-Breast Cancer and Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents.

BACKGROUND: The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to tamoxifen, the standard endocrine therapy for the disease, exacts continuous attention. To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profiles. OBJECTIVE: The primary goal of this study was to examine the potential of 1H-1,2,3-triazole linked quinolineisatin molecular hybrids as drug candidates against breast cancer and Methicillin-Resistant Staphylococcus aureus (MRSA) cells. METHODS: The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using Estrogen-Responsive (ER+) MCF-7 and MDA-MB-231 (Triple-Negative Breast Cancer -TNBC) cells, while antimicrobial efficacy was established via the broth dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney cells (HEK293) and human Red Blood Cells (hRBCs). In silico techniques were employed to predict the druglike properties of potent compounds and understand their binding modes with Estrogen Receptor alpha (ERα). RESULTS: Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50µM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDAMB- 231 and MRSA cells with IC50=71.40µM and MIC80=27.34µM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7-disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligandbinding domain of ERα. CONCLUSION: These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.

Therapeutic significance of ß-glucuronidase activity and its inhibitors: A review.

The emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, ß-glucuronidase (ßGLU) - a lysosomal acid hydrolase responsible for the catalytic deconjugation of ß-d-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of ßGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of ßGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved ßGLU inhibitory potency and the development of new therapeutic agents in consequential.

Amide Tethered 4-Aminoquinoline-naphthalimide Hybrids: A New Class of Possible Dual Function Antiplasmodials.

A series of amide tethered 4-aminoquinoline-naphthalimide hybrids has been synthesized to assess their in vitro antiplasmodial potential against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The most active and noncytotoxic compound had an IC50 value of 0.07 µM against W2 strain and was more active than standard antimalarial drugs, including chloroquine, desethylamodiaquine, and quinine, particularly for drug resistant malaria. The promising scaffold, when subjected to heme binding and molecular modeling studies, was identified as a possible potent inhibitor of hemozoin formation and P. falciparum chloroquine resistance transporter (PfCRT), respectively, and, therefore, could act as a dual function antiplasmodial.

Diastereoselective approach to rationally design tetrahydro-ß-carboline-isatin conjugates as potential SERMs against breast cancer.

A series of tetrahydro-ß-carboline-isatin conjugates, with varying substituents as well as stereochemistry at C-1 and C-5 position of tetrahydro-ß-carboline (THßC) and isatin ring, were prepared and assayed for anti-proliferative efficacy on Estrogen Responsive ER(+) (MCF-7) and ER(-ve) MDA-MB-231 cell-lines. The synthesized scaffolds displayed selective anti-proliferative efficacy against MCF-7 cell-line with the most active conjugate 8b exhibiting an IC50 value of 37.42 µM, comparable to that of peganumine A, a tetrahydro-ß-carboline analogue, isolated from Peganum harmala. The synthesized compound 8b was also more potent than the standard drug tamoxifen (IC50 = 50 µM against MCF-7). The observed activities were further corroborated via docking studies in ER-α (PDB ID: 3ERT).