Compounds 4j Research Articles

Design, syntheses and biological evaluation of natural product aiphanol derivatives and analogues: Discovery of potent anticancer agents

The natural product aiphanol (1) is one of the substances with anticancer biological activity isolated from traditional Chinese medicines (TCM) Smilax glabra Roxb. (Tufuling). Our recent research found that aiphanol could suppress angiogenesis and tumor growth by dual-blocking VEGF/VEGFRs and COX2 signal pathway. In this study, four series of 40 aiphanol derivatives and analogues were designed, synthesized and evaluated for their anticancer activity. Among them, the analogues 10j and 14c exhibited the most potent inhibition and broad-spectrum antiproliferative activity toward nine tumor cell lines. The IC50 values of the analogues 10j and 14c range from 0.81 to 10 μmol/L which up to 80-fold vs. parent compound aiphanol. The structure–activity relationship (SAR) studies indicated that the substrate at 7-position of benzo 1,4-dioxane is very crucial for anticancer activity. Molecular docking indicated that the compound 14c (ent-14c) tightly binds to VEGFR2 and COX2, respectively. Therefore, compounds 10j and 14c could be promising candidates for the development of anticancer agents in the future.

Synthesis and Anti-Tubercular Screening of 8-Benzyloxy-5-[2-(Substituted-Phenyl)-Thiazol-4-yl]-1H-Quinolin-2-One Derivatives

Novel 8-Benzyloxy-5-[2-(substituted-phenyl)-thiazol-4-yl]-1H-quinolin-2-one derivatives are synthesized by the cyclocondensation of substituted thiobenzamide and in-situ generated 8-benzyloxy-5-(2-bromo-acetyl)-1H-quinolin-2-one in the ethanol using simple one-pot multicomponent protocol under catalyst-free reaction conditions. All the products were screened for anti-tuberculosis (TB) activity against Mycobacterium tuberculosis H37Rv stains using L. J. medium conventional method and Compound 4h show good and Compound 4a, 4c, 4e, 4g, 4i, and 4j are also showing significant activity against M. tuberculosis.

Glyco-conjugation in 3-β-anhydroicaritine

A convenient method has been developed for the glycol-conjugation in 3-position of β-anhydroicaritine in a reasonable yield. The structure of the 3-glycosylated β-anhydroicaritine derivatives was confirmed to be correct by 1H NMR, 13C NMR and HRMS spectrum. These compounds are less soluble than icaritin, but more soluble than icariside II in CCl4. The screening results showed that compounds 12h, 12i and 12j had higher cytotoxicity to HepG2 and MCF-7 at a concentration of 50 μM.

Design, synthesis and biological evaluation of novel spiro-quinazolinone derivatives as chitin synthase inhibitors and antifungal agents

A series of spiro-quinazolinone scaffolds were constructed based on the bioactivity of quinazolinone and the inherent feature of spirocycle to design novel chitin synthase inhibitors that possess mode of action different from that of the currently used antifungal agents. Among them, the spiro[thiophen-quinazolin]-one derivatives containing α, β-unsaturated carbonyl fragments had shown inhibitory activities against chitin synthase and antifungal activities. The enzymatic experiments showed that among the sixteen compounds, compounds 12d, 12g, 12j, 12l and 12m exhibited inhibitions against chitin synthase with IC50 values of 116.7 ± 19.6 μM, 106.7 ± 14.2 μM, 102.3 ± 9.6 μM, 122.7 ± 22.2 μM and 136.8 ± 12.4 μM, respectively, which were comparable to that of polyoxin B (IC50 = 93.5 ± 11.1 μM). The assays of enzymatic Kinetic parameters showed that compound 12g was a non-competitive inhibitor of chitin synthase. The antifungal assays showed that compounds 12d, 12g, 12j, 12l and 12m exhibited a broad-spectrum of antifungal activity against the four strains tested in vitro. In which, compounds 12g and 12j had stronger antifungal activity against four tested strains than that of polyoxin B and similar to that of fluconazole, while compounds 12d, 12l and 12m showed antifungal activity comparable to that of polyoxin B against four tested strains. Meanwhile, compounds 12d, 12g, 12j, 12l and 12m exhibited good antifungal activity against fluconazole-resistant and micafungin-resistant fungi variants with MIC values ranging from 4 to 32 μg/mL while the MIC values of reference drugs were above 256 μg/mL. Furthermore, the results of drug-combination experiments showed that compounds 12d, 12g, 12j, 12l and 12m had synergistic or additive effects with fluconazole or polyoxin B. The results of sorbitol protection experiment and the experiment of antifungal activity against micafungin-resistant fungi further demonstrated that these compounds target chitin synthase. The result of cytotoxicity assay showed that compound 12g had low toxicity toward human lung cancer A549 cells and the ADME analysis in silico displayed that compound 12g possessed promising pharmacokinetic properties. The molecular docking indicated that compound 12g formed multiple hydrogen bond interactions binding to chitin synthase, which might be conductive to increasing the binding affinity and inhibiting the activity of chitin synthase. The above results indicated that the designed compounds were chitin synthase inhibitors with selectivity and broad-spectrum antifungal activity and could be act as the lead compounds against drug-resistant fungi.

Discovery of novel thiosemicarbazone derivatives with potent and selective anti-Candida glabrata activity

A series of 21 novel compounds containing a thiosemicarbazone moiety were designed and synthesised based on hit compound 1 from our in-house compound library screening. Most compounds showed potent antifungal activity in vitro against seven common pathogenic fungi. Notably, all compounds showed high potency against Candida glabrata 537 (MIC = ≤0.0156-2 µg/mL). Of note, compounds 5j and 5r displayed excellent antifungal activity against Candida krusei 4946 and Candida auris 922. Additionally, compounds 5j and 5r also showed high potency against 15 C. glabrata isolates with MIC values ranging from 0.0625 µg/mL to 4 µg/mL, with compound 5r being slightly superior to 5j. Moreover, compound 5r has certain effect against biofilm formation of C. glabrata. Furthermore, compound 5r has minimal cytotoxicity against HUVECs with an IC50 value of 15.89 µg/mL and no haemolysis at 64 µg/mL. Taken together, these results suggest that promising lead compound 5r deserves further investigation.

Design, synthesis and antimicrobial evaluation of benzimidazole containing 4-thiazolidinone based 5-arylidene derivatives

In an attempt to design a potent class of antimicrobials, we have synthesized benzimidazole derivatives based on 4-thiazolidinone which possessed 5-arylidenes 5a-o by using different catalysts under multistep conventional synthesis. Structures of the synthesized compounds have been established based on spectral data and compounds have been screened for their antimicrobial activity. Compound 5j shows maximum potency against all Gram-positive bacteria with a minimum inhibitory concentration (MIC) in the range of 25-50 μg/mL while moderate activity against Gram-negative bacterial strains is observed with a MIC value of 62.50 μg/mL. Compound 5n is found to be the most active against fungal strains with a MIC value of 250 μg/mL.

Synthesis, Antioxidant, Cytotoxicity, Induce Apoptosis Investigation and Docking Study of New Halogenated Dihydropyrano[3,2-b]Chromene-3-Carbonitrile Derivatives on MCF-7 Breast Cancer Cell Line.

Chromene derivatives showed numerous biological activities. In the current study, the antioxidant, cytotoxicity, and apoptosis properties of halogenated dihydropyrano[3,2-b]chromene-3-carbonitrile derivatives (HDCCD) on MCF-7 cell line have been examined. This study's principal point was synthesizing new halogenated pyranochromene derivatives and assessing their cytotoxic effects and apoptosis potential on MCF-7 breast cancer cell line by flow cytometry. Initially, 6-chloro- and 6-bromo-3-hydroxychromone compounds were prepared. In the next step, a series of HDCCD were synthesized by a one-pot three-component reaction of these two compounds, aromatic aldehydes, and malononitrile, in the presence of triethylamine in EtOH at reflux conditions. These compounds were fully characterized by standard spectroscopic techniques (IR, 1H, and 13C NMR) and elemental analyses. The potential of the antioxidant activity was determined by using ferric reducing antioxidant power assay (FRAP). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) were used to evaluate metabolic activity. The nitric oxide (NO) and malondialdehyde (MDA) biomarkers of the exposed cells were evaluated on the cells and their supernatant. To quantify apoptotic death of MCF-7 breast cancer cells treated by the compounds at their IC50 concentrations, Annexin V-FITC apoptosis detection kit was utilized. Molecular docking of compounds (6a-j) into the Cyclin-dependent kinase 6 (PDB code: 4EZ5) was carried out, and the probable binding mode of compounds 6e and 6j was determined. A dose-response relationship was seen in all the compounds. Most of them induced cytotoxic effects on the cells. Nitrite concentration of the culture media of the cells was decreased compared to the control. Malondialdehyde levels of the cells were below the range of the control by the addition of 6b, 6d, 6e, 6f, and 6g compounds on the cells, while the addition of the 6a, 6c, 6h, 6i, and 6j compounds increased the MDA level compared to the control. Flow cytometric analysis showed that most of the exposed cells were in the early and late apoptotic stage, and a few of them were in the necrotic stage. It could be concluded that HDCCD (6a-j) was toxic and caused death in the cells by apoptosis. The compounds have lipophilic characteristics, so they can easily pass the cell membrane. As confirmed by LDH results, it can be concluded that the cytotoxicity is connected with apoptosis rather than necrosis, endorsed by flowcytometry analysis afterward.

Synthesis, Antioxidant, Cytotoxicity, Induce Apoptosis Investigation and Docking Study of New Halogenated Dihydropyrano[3,2-b]Chromene-3-Carbonitrile Derivatives on MCF-7 Breast Cancer Cell Line

Background: Chromene derivatives showed numerous biological activities. In the current study, the antioxidant, cytotoxicity, and apoptosis properties of halogenated dihydropyrano[3,2-b]chromene-3-carbonitrile derivatives (HDCCD) on MCF-7 cell line have been examined. Objectives: This study's principal point was synthesizing new halogenated pyranochromene derivatives and assessing their cytotoxic effects and apoptosis potential on MCF-7 breast cancer cell line by flow cytometry. Methods: Initially, 6-chloro- and 6-bromo-3-hydroxychromone compounds were prepared. In the next step, a series of HDCCD were synthesized by a one-pot three-component reaction of these two compounds, aromatic aldehydes, and malononitrile, in the presence of triethylamine in EtOH at reflux conditions. These compounds were fully characterized by standard spectroscopic techniques (IR, 1H, and 13C NMR) and elemental analyses. The potential of the antioxidant activity was determined by using ferric reducing antioxidant power assay (FRAP). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) were used to evaluate metabolic activity. The nitric oxide (NO) and malondialdehyde (MDA) biomarkers of the exposed cells were evaluated on the cells and their supernatant. To quantify apoptotic death of MCF-7 breast cancer cells treated by the compounds at their IC50 concentrations, Annexin V-FITC apoptosis detection kit was utilized. Molecular docking of compounds (6a-j) into the Cyclin-dependent kinase 6 (PDB code: 4EZ5) was carried out, and the probable binding mode of compounds 6e and 6j was determined. Results: A dose-response relationship was seen in all the compounds. Most of them induced cytotoxic effects on the cells. Nitrite concentration of the culture media of the cells was decreased compared to the control. Malondialdehyde levels of the cells were below the range of the control by the addition of 6b, 6d, 6e, 6f, and 6g compounds on the cells, while the addition of the 6a, 6c, 6h, 6i, and 6j compounds increased the MDA level compared to the control. Flow cytometric analysis showed that most of the exposed cells were in the early and late apoptotic stage, and a few of them were in the necrotic stage. Conclusions: It could be concluded that HDCCD (6a-j) was toxic and caused death in the cells by apoptosis. The compounds have lipophilic characteristics, so they can easily pass the cell membrane. As confirmed by LDH results, it can be concluded that the cytotoxicity is connected with apoptosis rather than necrosis, endorsed by flowcytometry analysis afterward.

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[b,f]oxepine Derivatives.

Cancer is one of the most common causes of human death worldwide; thus, numerous therapies, including chemotherapy, have been and are being continuously developed. In cancer cells, an aberrant mitotic spindle-a microtubule-based structure necessary for the equal splitting of genetic material between daughter cells-leads to genetic instability, one of the hallmarks of cancer. Thus, the building block of microtubules, tubulin, which is a heterodimer formed from α- and β-tubulin proteins, is a useful target in anti-cancer research. The surface of tubulin forms several pockets, i.e., sites that can bind factors that affect microtubules' stability. Colchicine pockets accommodate agents that induce microtubule depolymerization and, in contrast to factors that bind to other tubulin pockets, overcome multi-drug resistance. Therefore, colchicine-pocket-binding agents are of interest as anti-cancer drugs. Among the various colchicine-site-binding compounds, stilbenoids and their derivatives have been extensively studied. Herein, we report systematic studies on the antiproliferative activity of selected stilbenes and oxepine derivatives against two cancer cell lines-HCT116 and MCF-7-and two normal cell lines-HEK293 and HDF-A. The results of molecular modeling, antiproliferative activity, and immunofluorescence analyses revealed that compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h were the most cytotoxic and acted by interacting with tubulin heterodimers, leading to the disruption of the microtubular cytoskeleton.

Design, synthesis and biological evaluation of thiazole and imidazo[1,2-a]pyridine derivatives containing a hydrazone substructure as potential agrochemicals

Agricultural chemicals with multifunctional applications in crop protection have attracted increasing attention. Herein, two new series of thiazole and imidazo[1,2-a]pyridine derivatives containing a hydrazone substructure were designed and synthesized via a concise synthesis route. Bioassay results showed that most of the thiazole derivatives exhibited broad-spectrum fungistatic activities, which were exemplified by compounds 1c, 1e, 1g, 1h and 1j. In particular, compound 1e displayed excellent in vitro inhibitory effects with the EC50 values of 5.00, 18.24, 6.94, and 3.03 μg/mL against the fungi Botrytis cinerea, Cytospora sp, Fusarium graminearum, and Fusarium solani, respectively. Detached fruit experiments against tomato gray mold (caused by B. cinerea) in vivo revealed that the control efficiency of compound 1e at 10, 20 and 40 μg/mL for 5 days was 35.05%, 54.14% and 81.83%, respectively, which was comparable and even superior to that of the fungicide carbendazim. Additionally, the title compounds also showed remarkable larvicidal activity against M. separata and some compounds exhibited good aphicidal activity. In a word, the bioassay indicated that a certain number of title compounds had multiple biological activities. Given their excellent antifungal and larvicidal characteristics, these interesting derivatives based on the title compounds could be served as new scaffolds for the development of pesticide with multifunctional applications.

Novel carboxamide and carbohydrazide functionalized pyridopyrimidine derivatives and their anticancer activity

A series of novel carboxamide and carbohydrazide functionalized pyridopyrimidine derivatives was prepared starting from 6-methyl/ethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile 1. Compound 1 on reaction with sulphuric acid gave compound 2. Compound 2 on reaction with chloroacetamide followed by reaction with EMME coupling and further cyclization gave compound 5. Compound 5 on reaction with hydrazine hydrate produced hydrazide derivatives 6. Compound 6 on reaction with diverse substituted aromatic aldehyde gave Schiff’s base derivatives 7a-j. Ester derivatives 5 on reaction with different aliphatic amine gave carboxamide derivatives 8a-f. All the final 7a-j and 8a-f compounds were evaluated for anti cancer activity against four human cancer cell lines such as HeLa - Cervical cancer (CCL-2), COLO 205- Colon cancer (CCL-222); HepG2- Liver cancer (HB-8065), MCF7 - Breast cancer (HTB-22) and promising compounds 7e, 7h and 7j have been identified.

Design, Synthesis, and Antifungal/Antioomycete Activity of Thiohydantoin Analogues Containing Spirocyclic Butenolide.

Novel fungicidal agents were designed based on the combination of two privileged scaffolds, thiohydantoin and spirocyclic butenolide, which are widely found in natural products. The synthesized compounds were characterized by 1H NMR, 13C NMR, and high-resolution electrospray ionisation mass spectrometry. The in vitro antioomycete activity evaluation showed that most of the compounds exhibited excellent inhibitory activities against different developmental stages in the life cycle of pathogenic oomycete Phytophthora capsici. Compound 5j could inhibit the mycelial growth, sporangium production, zoospore release, and cystospore germination significantly with EC50 values of 0.38, 0.25, 0.11, and 0.026 μg/mL, respectively. The in vivo antifungal/antioomycete bioassay results revealed that the series of compounds generally showed outstanding control efficacies against the pathogenic oomycete Pseudoperonospora cubensis, and compounds 5j, 5l, 7j, 7k, and 7l possessed broad-spectrum antifungal activities against the test phytopathogens. The in vivo protective and curative efficacies against P. capsici of the representative compound 5j were excellent, which were better than those of azoxystrobin. More prominently, 5j significantly promoted the biomass accumulation of the root system and reinforced the cell wall by callose deposition. The pronounced upregulation of immune response-related genes indicated that the active oomycete inhibitor 5j also functioned as a plant elicitor. Transmission electron microscopy observation and the enzyme activity test demonstrated that the mechanism of action of 5j was to bind to the pivotal protein, complex III on the respiratory chain, which resulted in a shortage of energy supply. Molecular docking results exhibited that compound 5j appropriately matched with the Qo pocket and had no interaction with the most commonly mutated site Gly-142, which may be of significant benefit in Qo fungicide resistance management. Compound 5j showed great advantages and potential in oomycete control, resistance management, and induction of disease resistance. A further investigation of 5j with a unique structure might have direct implications for the creation of novel oomycete inhibitors against plant-pathogenic oomycetes.

Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

Pyrazole derivatives of pyridine and naphthyridine as proapoptotic agents in cervical and breast cancer cells

Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.

4-Adamantyl-(2-(arylidene)hydrazinyl)thiazoles As Potential Antidiabetic Agents: Experimental and Docking Studies

Aim: To develop an efficient and cost-effective antidiabetic agent. Methods: A simple and convenient Hantzsch synthetic strategy was used to prepare 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. Results: Fifteen newly established structures of 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles were tested for their α-amylase, antiglycation and antioxidant activities. Almost all tested compounds showed excellent α-amylase inhibition. Compounds 3a and 3j exhibited the highest potency, with IC50 values of 16.34±2.67 and 16.64±1.12μM, respectively. Compounds 3c and 3i exhibited comparable antiglycation potential with the standard, aminoguanidine. The antioxidant potential of compound 3g was found to be excellent, with an IC50 value of 28.19±0.2563μM. The binding interactions of compound 3a (binding energy=-8.833kcal/mol) with human pancreatic α-amylase identified 3a as a potent α-amylase inhibitor. Conclusion: Enrichment of established structures with more electron-donating functionalities may assist/lead to the development of more potent antidiabetic drugs.

Antioxidant and Anticholinesterase Potentials of Novel 4,6-Dimethoxyindole based Unsymmetrical Azines: Synthesis, Molecular Modeling, In Silico ADME Prediction and Biological Evaluations

Chemically and biologically important -C = N-N = C- diimine linkage was used to build unsymmetrical azine systems with indole heterocyclic backbone and substituted aromatic carbaldehydes. Ten novel compounds 7a-j were synthesized by the Schiff base reaction of 4,6-dimethoxyindole-7-hydrazone 5 and a range of substituted carbaldehydes 6a-j with high yields and purities. The biological study was directed to identify the antioxidant potentials due to the expected electronic delocalization capability of designated linkage which is important for possible hydrogen or electron donation. The three different assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization and CUPRAC (cupric reducing antioxidant capacity) were employed to detect the antioxidant properties. The antioxidant potentials were found to be moderate for ABTS and CUPRAC assays and the compound 7j was the most potent candidate for all the antioxidant assays. More importantly, the anticholinesterase properties were investigated by acetylcholinesterase (ACh) and butyrylcholinesterase (BCh) enzyme inhibition assays. The molecular docking studies were also carried out to determine the possible poses of ligands 7a-j in binding sites of enzymes and ligand-residue interactions. The synthesized compounds were found to be more effective for the anticholinesterase activity with three promising candidates 7d, 7h and 7j in the case of BChE inhibitions. The compound 7h was determined as the best candidate with the comparable IC50 values for AChE and better inhibition potency for BChE with 7j. A range of hydrophobic and hydrophilic interactions were detected for the designated compound 7h and 7j through different amino acid residues and the computational results were found to be compatible with the biological counterparts.

One-Pot Synthesis and Evaluation of Antioxidative Stress and Anticancer Properties of an Active Chromone Derivative.

Chromones are the structural building blocks of several natural flavonoids. The synthesis of chromones, which contain a hydroxy group on the ring, presents some challenges. We used the one-pot method to synthesize ten chromone derivatives and two related compounds using modified Baker-Venkataraman reactions. The structures were confirmed using FT-IR, 1H NMR, 13C NMR, and HRMS. The in vitro antioxidant assay revealed that compounds 2e, 2f, 2j, and 3i had potent antioxidant activity and that all these synthesized compounds, except those containing nitro groups, were harmless to normal cells. In addition, compounds 2b, 2d, 2e, 2f, 2g, 2i, and 2j had anticancer activity. Compounds 2f and 2j were used to investigate the mechanism of anticancer activity. Both 2f and 2j induced a slightly early apoptotic effect but significantly impacted the S phase in the cell cycle. The effect on cell invasion indicates that both compounds significantly inhibited the growth of cervical cancer cells. A chromone scaffold possesses effective chemoprotective and antioxidant properties, making it a promising candidate for antioxidant and future cancer treatments.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of > 20 µM < 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 > 125 µM).

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

DESIGN, SYNTHESIS, MOLECULAR DOCKING STUDIES AND ANTICANCER ACTIVITY OF 5-SUSTITUTED-3-((2-(4-NITROPHENYL) THIAZOL-4-YL) IMINO)-1-(SUBSTITUTED-1-YLMETHYL) INDOLIN-2-ONE SCAFFOLDS

A new series of 5-sustituted-3-((2-(4-nitrophenyl) Thiazol-4-yl) Imino)-1-(substituted-1-ylmethyl) Indolin-2-one derivatives (3a-3l) are synthesized by conventional method. All synthesized compounds were characterized via IR, 1H-NMR, 13C-NMR and MASS spectral analysis. Compounds were evaluated for their anticancer activity against MCF-7 cell lines and antibacterial activity against Staphylococcus aureus, Bacillus subtilis, E. Coli and Salmonella paratyphi. These results indicated that compound 3a, 3e, 3f and 3j showed good activity compared to the standard drug. Synthesized target molecules exhibited anticancer activity against breast cancer cell lines with IC50 values of range from 60.21. to 130.21 μg. Compound 3c (60.21μg) showed good activity compared with doxorubicin. Compounds were subjected to molecular docking studies with estrogen receptor (ER) epidermal growth factor receptor (EGFR) with PDB ID:3ERT. Among the docked ligands, compound 3a and 3e reported highest docking score (-8.512, -6.869) with glide binding energy (-43.785, -24.187).