Synthesis, Antitumor Activities and Molecular Modelling of 4-Anilinoquinazoline Derivatives as EGFR-TK Inhibitors

New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly, derivatives 8a, 8f and 9 with IC50 values of 0.14±0.003, 0.119±0.003, and 0.115±0.002 μM, respectively, showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3 and LS-174T cell lines. Multikinase enzymes inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK which also had resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell cycle analyses of MCF-7 cells treated with 8a and 9 was measured in addition to other related factors such as Bax, Bcl-2, caspase-9, and PARP-1.

Therapeutic enzymes as non-conventional targets in cardiovascular impairments:A Comprehensive Review

Over the last few decades, substantial progress has been made towards the understanding of cardiovascular diseases (CVDs). In-depth mechanistic insights have also provided opportunities to explore novel therapeutic targets and treatment regimens to be discovered. Therapeutic enzymes are an example of such opportunities. The balanced functioning of such enzymes protects against a variety of CVDs while on the other hand, even a small shift in the normal functioning of these enzymes may lead to deleterious outcomes. Owing to the great versatility of these enzymes, inhibition and activation are key regulatory approaches to counter the onset and progression of several cardiovascular impairments. While cardiovascular remedies are already available in excess and of course they are efficacious, a comprehensive description of novel therapeutic enzymes to combat CVDs is the need of the hour. In light of this, the regulation of the functional activity of these enzymes also opens a new avenue for the treatment approaches to be employed. This review describes the importance of non-conventional enzymes as potential candidates in several cardiovascular disorders while highlighting some of the recently targeted therapeutic enzymes in CVDs.

In-Vitro Antidiabetic Effect of Ziziphus mucronata Leave Extracts

Background: Diabetes is a metabolic disorder characterized by hyperglycemia due to the body’s inability to produce insulin or inaction of the produced insulin or a combination of both. One antidiabetic therapeutic approach is to reduce gastrointestinal glucose production and absorption through the inhibition of carbohydrate digesting enzymes such as alpha-amylase as well as through the inhibition of hemoglobin glycosylation. Objective: This study sets out to evaluate the in vitro antidiabetic activity of Ziziphus mucronata extracts for their effect on alpha-amylase and glycosylation of hemoglobin. Methods: Successive gradient maceration of Z. mucronata leaves were carried out using Hexane, Acetone, Methanol and separately with water to obtain four (4) extracts labelled HE, AE, ME, and WE respectively. These were subjected to in vitro studies for their inhibitory effect on alpha-amylase and hemoglobin glycosylation, Standard laboratory methods were used to screen for phytochemicals of the most potent extract. Results: The result showed that AE, ME and WE extract exhibited a dose-dependent increase in percentage inhibition of both alpha-amylase and hemoglobin glycosylation. However, on a stricking note, the AE showed a more potent data result with percentage (%) potency of 71.02 at 1mg/ml, the lowest glucose concentration (of 25mg/ml) at 0.242nm as well as the highest hemoglobin glycosylation inhibitory mean concentration of 3.663nm after 72 hours. The AE of Z. mucronata (the most potent) revealed the presence of alkaloids, anthraquinone, glycosides, flavonoids, phenols, saponin, tanins and terpenoids. Conclusion: Thus, the Acetone extract is more likely to give a lead antidiabetic drug molecule of drug when further explored; which somewhat justify the folkloric claims of Z. mucronata leave as an antidiabetic. Keywords: Heamoglabin glycosylation, Alpha-amylase enzymes, Inhibition, Glucose.

Barbeya oleoides Leaves Extracts: In Vitro Carbohydrate Digestive Enzymes Inhibition and Phytochemical Characterization

This study investigated the in vitro inhibitory potential of different solvent extracts of leaves of Barbeya oleoides on key enzymes related to type 2 diabetes mellitus (α-glucosidase and α-amylase) in combination with an aggregation assay (using 0.01% Triton X-100 detergent) to assess the specificity of action. The methanol extract was the most active in inhibiting α-glucosidase and α-amylase, with IC50 values of 6.67 ± 0.30 and 25.62 ± 4.12 µg/mL, respectively. However, these activities were significantly attenuated in the presence of 0.01% Triton X-100. The chemical analysis of the methanol extract was conducted utilizing a dereplication approach combing LC-ESI-MS/MS and database searching. The chemical analysis detected 27 major peaks in the negative ion mode, and 24 phenolic compounds, predominantly tannins and flavonol glycosides derivatives, were tentatively identified. Our data indicate that the enzyme inhibitory activity was probably due to aggregation-based inhibition, perhaps linked to polyphenols.

Chemicals Constituents of the Algerian Glycyrrhiza glabra L. Root Extracts and their Antioxidant, Antibacterial and Anticholinesterase Activities

Background: Glycyrrhiza glabra L. is an important medicinal plant endowed with various pharmacological virtues. This study aimed to investigate the antioxidant, antibacterial, and anticholinesterase activities of the Algerian Glycyrrhiza glabra L. roots extracts. Methods: The chemical composition of both chloroformic (LCh) and ethyl acetate (LAE) extracts were analyzed by RP-HPLC-PDA and 1H NMR spectroscopy. The antioxidant activity was evaluated using hydrogen atoms transfer methods (DPPH) and single electron transfer (ABTS and CUPRAC assays). The antibacterial activity was realized against different strains via the Minimal Inhibitory Concentration (MIC), when the anticholinesterase activity was performed through the acetylcholinesterase and butyrylcholinesterase enzymes inhibition. Results: The chemical analysis revealed the presence of phenolic acids (gallic acid, p-coumaric acid) and a hydroxycinnamic compound (ferulic acid). However, flavonoids were represented by quercetin, rutin (flavonol), and glabridin (isoflavane). The 1H NMR of the L4 fraction from LCh extract allowed to characterize the structure of glabridin. : The antioxidant assays revealed that LCh extract is the best among other extracts with IC50 DPPH of 33.94 μg/mL, IC50 ABTS of 3.45 μg/mL and CUPRAC A0.5 of 21.78 μg/mL. The LCh extract displayed an effective antibacterial activity with MIC’s of 19.5 μg/mL against seven gram positive and negative bacteria strains. The same extract showed a potent butyrylcholinesterase inhibitory activity with IC50= 4.72 ± 0.72 μg/mL, which is too strong than the standard drug. Conclusion: The study demonstrated that G. glabra root extracts had a high antibacterial, and free radical scavenging. It was also able to inhibit cholinesterase enzymes, which confirm the effectiveness of phytoconstituents present in the plant, especially flavonoids.