Design,synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators

In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC₅₀=2.25 µM) and U239 (IC₅₀=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC₅₀=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC₅₀=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4^CRBN. These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.     

Drimanes from Drimys brasiliensis with leishmanicidal and antimalarial activity

This paper evaluates CHCl₃ and CH₃OH extracts of the stem bark, branches and leaves of Drimys brasiliensis and drimane sesquiterpenes isolated from the stem bark against strains of Leishmania amazonensis and Leishmania braziliensis promastigotes and Plasmodium falciparum trophozoites. All of the extracts and compounds were tested in cell lines in comparison with reference standards and cell viability was determined by the XTT method. The CHCl₃ and CH₃OH extracts from the stem bark and branches yielded promising results against two strains of Leishmania, with 50% inhibitory concentrations (IC₅₀ ) values ranging from 39-100 µg/mL. The CHCl₃ extract of the stem bark returned IC₅₀ values of 39 and 40.6 µg/mL for L. amazonensis and L. braziliensis, respectively. The drimanes were relatively effective: 1-β-(p-coumaroyloxy)-polygodial produced IC₅₀ values of 5.55 and 2.52 µM for L. amazonensis and L. braziliensis, respectively, compared with 1-β-(p-methoxycinnamoyl)-polygodial, which produced respective IC₅₀ values of 15.85 and 17.80 µM. The CHCl₃ extract demonstrated activity (IC₅₀ of 3.0 µg/mL) against P. falciparum. The IC₅₀ values of 1-β-(p-cumaroyloxyl)-polygodial and 1-β-(p-methoxycinnamoyl)-polygodial were 1.01 and 4.87 µM, respectively, for the trophozoite strain. Therefore, the results suggest that D. brasiliensis is a promising plant from which to obtain new and effective antiparasitic agents.     

In vitro and in silico studies of bis (indol-3-yl) methane derivatives as potential α-glucosidase and α-amylase inhibitors

In this paper, bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated for their inhibitory activity against α-glucosidase and α-amylase. All synthesised compounds showed potential α-glucosidase and α-amylase inhibitory activities. Compounds 5 g (IC₅₀: 7.54 ± 1.10 μM), 5e (IC₅₀: 9.00 ± 0.97 μM), and 5 h (IC₅₀: 9.57 ± 0.62 μM) presented strongest inhibitory activities against α-glucosidase, that were ∼ 30 times stronger than acarbose. Compounds 5 g (IC₅₀: 32.18 ± 1.66 µM), 5 h (IC₅₀: 31.47 ± 1.42 µM), and 5 s (IC₅₀: 30.91 ± 0.86 µM) showed strongest inhibitory activities towards α-amylase, ∼ 2.5 times stronger than acarbose. The mechanisms and docking simulation of the compounds were also studied. Compounds 5 g and 5 h exhibited bifunctional inhibitory activity against these two enzymes. Furthermore, compounds showed no toxicity against 3T3-L1 cells and HepG2 cells.

Highlights

1. A series of bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated inhibitory activities against α-glucosidase and α-amylase.
2. Compound 5g exhibited promising activity (IC₅₀ = 7.54 ± 1.10 μM) against α-glucosidase.
3. Compound 5s exhibited promising activity (IC₅₀ = 30.91 ± 0.86 μM) against α-amylase.
4. In silico studies were performed to confirm the binding interactions of synthetic compounds with the enzyme active site.

     

Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC₅₀: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC₅₀: 0.31 µM) and f14 (IC₅₀: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4–8 µg/mL), non-toxic to HUVEC and HepG2 (CC₅₀: approximately 50 µM), and metabolically stable (t_1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.     

Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC₅₀ values (0.002 − 0.004 µM) comparing to Staurosporine of IC₅₀; 0.005 μM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC₅₀ range 0.0149 − 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-β, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-β of IC₅₀ values 0.17 × 10⁻³, 0.07 × 10⁻³ µM in comparison with the reference drug sorafenib of IC₅₀; 0.28 × 10⁻³, 0.13 × 10⁻³ µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.     

Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

Nine compounds (MO1–MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC₅₀ value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC₅₀ = 6.1 µM), followed by MO9 (IC₅₀ = 12.01 µM) and MO7 most potently inhibited MAO-A (IC₅₀ = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (K_i = 0.018 µM); MO5 reversibly competitively inhibited AChE (K_i = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (K_i = 7.04 µM). MO1, MO5 and MO9 crossed the blood–brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer’s disease.     

Design,synthesis and molecular docking of new fused 1H-pyrroles,pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

A new series of 1H-pyrrole (6a–c, 8a–c), pyrrolo[3,2-d]pyrimidines (9a–c) and pyrrolo[3,2-e][1, 4]diazepines (11a–c) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC₅₀ values ranging from 0.009 to 2.195 µM. IC₅₀ value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC₅₀ values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC₅₀ value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10–23% compared to imatinib (1–10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.     

Inhibition of Leishmania (Leishmania) amazonensis and Rat Arginases by Green Tea EGCG, (+)-Catechin and (?)-Epicatechin: A Comparative Structural Analysis of Enzyme-Inhibitor Interactions

Epigallocatechin-3-gallate (EGCG), a dietary polyphenol (flavanol) from green tea, possesses leishmanicidal and antitrypanosomal activity. Mitochondrial damage was observed in Leishmania treated with EGCG, and it contributed to the lethal effect. However, the molecular target has not been defined. In this study, EGCG, (+)-catechin and (−)-epicatechin were tested against recombinant arginase from Leishmania amazonensis (ARG-L) and rat liver arginase (ARG-1). The compounds inhibit ARG-L and ARG-1 but are more active against the parasite enzyme. Enzyme kinetics reveal that EGCG is a mixed inhibitor of the ARG-L while (+)-catechin and (−)-epicatechin are competitive inhibitors. The most potent arginase inhibitor is (+)-catechin (IC₅₀ = 0.8 µM) followed by (−)-epicatechin (IC₅₀ = 1.8 µM), gallic acid (IC₅₀ = 2.2 µM) and EGCG (IC₅₀ = 3.8 µM). Docking analyses showed different modes of interaction of the compounds with the active sites of ARG-L and ARG-1. Due to the low IC₅₀ values obtained for ARG-L, flavanols can be used as a supplement for leishmaniasis treatment.     

Molecular modeling of Ruellia tuberosa L compounds as a-amylase inhibitor: an in silico comparation between human and rat enzyme model

Inhibition of α-amylase is an important strategy to control post-prandial hyperglycemia. The present study on Ruellia tuberosa, known as traditional anti-diabetic agent, is being provided in silico study to identify compounds inhibiting α-amylase in rat and human. Compounds were explored from PubChem database. Molecular docking was studied using the autodock4. The interactions were further visualized and analyzed using the Accelrys Discovery Studio version 3.5. Binding energy of compounds to α-amylase was varying between -1.92 to -6.66 kcal/mol in rat pancreatic alpha amylase and -3.06 to -8.42kcal/mol in human pancreatic alpha amylase, and inhibition konstanta (ki) was varying between 13.12- 39460µM in rat and 0.67-5600µM in human. The docking results verify that betulin is the most potential inhibitor of all towards rat model alpha amylase and human alpha amylase. Further analysis reveals that betulin could be a potential inhibitor with non-competitive pattern like betulinic acid. In comparison, betulin has smaller Ki (0.67µM) than acarbose (2.6 µM), which suggesting that betulin is more potential as inhibitor than acarbose, but this assumption must be verified in vitro.     

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Trypanothione synthetase (TryS) catalyses the synthesis of N¹,N⁸-bis(glutathionyl)spermidine (trypanothione), which is the main low molecular mass thiol supporting several redox functions in trypanosomatids. TryS attracts attention as molecular target for drug development against pathogens causing severe and fatal diseases in mammals. A drug discovery campaign aimed to identify and characterise new inhibitors of TryS with promising biological activity was conducted. A large compound library (n = 51,624), most of them bearing drug-like properties, was primarily screened against TryS from Trypanosoma brucei (TbTryS). With a true-hit rate of 0.056%, several of the TbTryS hits (IC₅₀ from 1.2 to 36 µM) also targeted the homologue enzyme from Leishmania infantum and Trypanosoma cruzi (IC₅₀ values from 2.6 to 40 µM). Calmidazolium chloride and Ebselen stand out for their multi-species anti-TryS activity at low µM concentrations (IC₅₀ from 2.6 to 13.8 µM). The moieties carboxy piperidine amide and amide methyl thiazole phenyl were identified as novel TbTryS inhibitor scaffolds. Several of the TryS hits presented one-digit µM EC₅₀ against T. cruzi and L. donovani amastigotes but proved cytotoxic against the human osteosarcoma and macrophage host cells (selectivity index ≤ 3). In contrast, seven hits showed a significantly higher selectivity against T. b. brucei (selectivity index from 11 to 182). Non-invasive redox assays confirmed that Ebselen, a multi-TryS inhibitor, induces an intracellular oxidative milieu in bloodstream T. b. brucei. Kinetic and mass spectrometry analysis revealed that Ebselen is a slow-binding inhibitor that modifies irreversible a highly conserved cysteine residue from the TryS’s synthetase domain. The most potent TbTryS inhibitor (a singleton containing an adamantine moiety) exerted a non-covalent, non-competitive (with any of the substrates) inhibition of the enzyme. These data feed the drug discovery pipeline for trypanosomatids with novel and valuable information on chemical entities with drug potential.     

Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer

In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (5a–i) and ureas (8a–y) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as the most potent anti-proliferative analogue against TNBC MDA-MB-231 cells with IC₅₀ equals 18.7 µM, which is better than that of piperine (IC₅₀ = 47.8 µM) and 5-FU (IC₅₀ = 38.5 µM). Furthermore, 8q was investigated for its possible mechanism of action in MDA-MB-231 cells via Annexin V-FITC apoptosis assay and cell cycle analysis. Moreover, an in-silico analysis has proposed VEGFR-2 as a probable enzymatic target for piperine-based derivatives, and then has explored the binding interactions within VEGFR-2 active site (PDB:4ASD). Finally, an in vitro VEGFR-2 inhibition assay was performed to validate the in silico findings, where 8q showed good VEGFR-2 inhibitory activity with IC₅₀ = 231 nM.     

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC₅₀=25.6 µM, anti-angiogenesis in Zebrafish: IC₅₀=38.4 µM, anti-proliferation against K562 and Jurkat: IC₅₀=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC₅₀=4.8 µM and anti-angiogenesis in Zebrafish: IC₅₀=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC₅₀= 0.09–1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

The anti-oxidative,anti-cell proliferative and anti-microbial efficacies of cold-adapted Crepis flexuosa: HPTLC and GC/MS analyses

The genus Crepis constitutes cold-adapted plant spp., of these some are traditionally used in folk medicine against inflammation or fungal infections without scientific validations. Here, we report the biological activities of Crepis flexuosa total ethanol-extract (CF-EtOH) and its hexane (CF-Hex), ethyl acetate (CF-EtOA), butanol (CF-ButOH), and aqueous (CF-Aqua) fractions. Our in vitro DPPH and ABTS radical-scavenging assays showed CF-EtOH, CF-ButOH and CF-Aqua with maximal, CF-EtOA with moderate, and CF-Hex with mild anti-oxidant activities. When tested on human cancer cell lines, high cytotoxicity was demonstrated by CF-EtOH (IC₅₀: 42.45 μg/ml) and CF-Aqua (IC₅₀: 46.37 μg/ml) on HepG2, followed by CF-Hex (IC₅₀: 63.24 μg/ml) and CF-ButOH (IC₅₀: 65.32 μg/ml) on MCF7 cells. The human primary cell line (HUVEC) had comparatively lower cytotoxicity for the tested samples. Moreover, when assessed for anti-microbial efficacy, CF-ButOH and CF-Aqua exhibited the strongest activity (MIC: 156.25 μg/ml) against S. aureus, E. faecalis and C. albicans. Further, while the developed RP-HPTLC identified the bioactive flavonoid luteolin-7-O-glucoside (17.58 mg/g), GS/MS analysis revealed sixteen compounds in C. flexuosa extract. In conclusion, we for the first time show the promising anti-oxidative, anti-cell proliferative and anti-microbial efficacies of C. flexuosa. This warrants further phytochemical and bio-efficacy studies towards isolations and identifications of active principles.     

Diaryl azo derivatives as anti-diabetic and antimicrobial agents: synthesis,in vitro,kinetic and docking studies

In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC₅₀ (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.     

Imbricaric Acid and Perlatolic Acid: Multi-Targeting Anti-Inflammatory Depsides from Cetrelia monachorum

In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E₂ synthase-1 and nuclear factor kappa B revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. As conceivable source for novel anti-inflammatory compounds. Phytochemical investigation of the ethanolic crude extract resulted in the isolation and identification of 11 constituents, belonging to depsides and derivatives of orsellinic acid, olivetolic acid and olivetol. The two depsides imbricaric acid (4) and perlatolic acid (5) approved dual inhibitory activities on microsomal prostaglandin E₂ synthase-1 (IC₅₀ = 1.9 and 0.4 µM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC₅₀ = 5.3 and 1.8 µM, resp.) and on purified enzyme (IC₅₀ = 3.5 and 0.4 µM, resp.). Additionally, these two main constituents quantified in the extract with 15.22% (4) and 9.10% (5) showed significant inhibition of tumor necrosis factor alpha-induced nuclear factor kappa B activation in luciferase reporter cells with IC₅₀ values of 2.0 and 7.0 µM, respectively. In a murine in vivo model of inflammation, 5 impaired the inflammatory, thioglycollate-induced recruitment of leukocytes to the peritoneum. The potent inhibitory effects on the three identified targets attest 4 and 5 a pronounced multi-target anti-inflammatory profile which warrants further investigation on their pharmacokinetics and in vivo efficacy.     

Design,synthesis, and analysis of antiproliferative and apoptosis-inducing activities of nitrile derivatives containing a benzofuran scaffold: EGFR inhibition assay and molecular modelling study

New cyanobenzofurans derivatives 2–12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC₅₀ = 4.17–8.87 and 5.5–11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC₅₀ = 16.08–23.67 µM), HCT-116 (IC₅₀ = 8.81–13.85 µM), and MCF-7 (IC₅₀ = 8.36–17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC₅₀ = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC₅₀ of 0.81–1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.     

Discovery of new quinolines as potent colchicine binding site inhibitors: design,synthesis, docking studies,and anti-proliferative evaluation

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC₅₀ = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20, 21, 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC₅₀ values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC₅₀ values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC₅₀ = 10.6 nM) and CA-4 (IC₅₀ = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.     

Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC₅₀ (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC₅₀ (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC₅₀ > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC₅₀ =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC₅₀ ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC₅₀=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.     

Rational Design,Synthesis, and Biological Evaluation of Third Generation α-Noscapine Analogues as Potent Tubulin Binding Anti-Cancer Agents

Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol) than the parent compound, noscapine (-5.505 kCal/mol) and its existing derivatives (-5.563 to -6.412 kCal/mol). Free energy (ΔG _bind) calculations based on the linear interaction energy (LIE) empirical equation utilizing Surface Generalized Born (SGB) continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol). Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol). The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl) noscapine (6f) binds tubulin with highest binding affinity (K_D, 38 ± 4.0 µM), which is ~ 4.0 times higher than that of the parent compound, noscapine (K_D, 144 ± 1.0 µM) and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (K_D, 54 ± 9.1 µM). All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC₅₀ values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC₅₀ values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents.