Hatem A. Abuelizz

Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives

A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1–24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.

Synthesis and anticancer activity of new quinazoline derivatives

In this study, a new series of quinazoline derivatives (3–26) was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5-methylbenzoic acid with butyl isothiocyanate resulted in the new 2-thioxoquinazolin-4-one (3). Alkylation and hydrazinolysis of the inherent thioxo group in (1–3) afforded the corresponding thioethers (4–23) and hydrazine derivatives (24 and 25), then 24 was further transformed into tricyclic derivative 26 via cyclocondensation reaction. Compounds 1 and 2, which were previously synthesized, were found to exhibit anticancer activity. The cytotoxicity of all compounds was evaluated in vitro against the HeLa and MDA-MB231 cancer cell lines, including 1 and 2 for comparison, using MTT assay. The treatment of the cells was performed with the synthesized compounds and gefitinib at 0, 1, 5, 10, 25, and 50 μM and incubated for 24 h in 50% DMSO. The IC50 values of the target compounds were reported in μM, using gefitinib as a standard. Our results indicated that all compounds exhibited significant in vitro cytotoxicity against both cell lines. While compounds 1–3 showed good activity, compounds 21–23 were found to be more potent than gefitinib. Thus, compounds 21–23 may be potential anticancer agents, with IC50 values ranging from 1.85 to 2.81 μM in relation to gefitinib (IC50 = 4.3 and 28.3 μM against HeLa and MDA-MB231 cells, respectively).

Antimicrobial Activity of New 2-Thioxo-benzo[g]quinazolin-4(3H)-one Derivatives

BACKGROUND The antimicrobial activity of a synthesized series of 28 2-thioxobenzo[ g]quinazolin-4(3H)-one derivatives was evaluated in vitro against five Gram-positive bacteria, including Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes. The antibacterial activity was extended to include five Gramnegative bacteria: Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Klebsiella oxytoca and Enterobacter cloacae. Furthermore, the antifungal activity was evaluated against 10 fungal strains, including Aspergillus fumigatus, Syncephalastrum racemosum, Geotricum candidum, Candida albicans, Aspergillus niger, Cryptococcus neoformans, Candida tropicalis, Penicillium expansum, Microsporum canis and Trichophyton mentagrophytes. METHODS The agar well diffusion method was adopted against Gram-positive and Gram-negative bacteria and fungi, using ampicillin, gentamicin and amphotericin B as reference drugs, respectively. RESULTS The findings of the antibacterial studies revealed that most of the tested compounds possess strong activity against both bacterial species. Compounds 8 and 23 were the most active on Grampositive bacteria, while several compounds demonstrated significant antibacterial activity on Gramnegative bacteria, especially Escherichia coli. Furthermore, several compounds showed strong antifungal activity against many of the investigated fungi. The obtained results were reinforced by determination of the minimum inhibitory concentration for the active compounds against Grampositive and Gram-negative bacteria, as well as fungi, compared to the reference drugs. CONCLUSION Many of the investigated compounds showed potent activity against all tested microbial species. The discovery has provided a foundation for the synthesized compounds to serve as a platform for further design and development of more potent antimicrobial agents.

In vitro evaluation of new 2-phenoxy-benzo[g][1,2,4]triazolo[1,5-a]quinazoline derivatives as antimicrobial agents

Previously, seventeen 2-phenoxy-benzo[g][1,2,4]triazolo[1,5-a]quinazoline derivatives were prepared and characterized by physicochemical and spectral means. This study was conducted to evaluate their activities in vitro against five Gram-negative and five Gram-positive of clinically pathogenic bacterial strains and ten fungal strains. The antimicrobial activity was assessed, and the minimum inhibitory concentration values of the tested compounds were determined in μg ml-1, using the diffusion agar technique. The bacterial strains used were Escherichia coli (ATCC 25922), Proteus mirabilis (ATCC 7002), Klebsiella oxytoca (ATCC 700324), Pseudomonas aeruginosa (ATCC 10145), Enterobacter cloacae (ATCC 13047D-5), Bacillus subtilis (NRRL B-543), Enterococcus faecalis (RCMB 0100154-2), Staphylococcus aureus (ATCC 29213), Staphylococcus epidermidis (ATCC 12228), and Streptococcus pyogenes (RCMB 0100174-2). Aspergillus fumigatus (RCMB 02568), Syncephalastrum racemosum (IMI 21178), Geotricum candidum (IMI 329542), Candida albicans (ATCC 10231), Aspergillus niger (IMI 130783), Cryptococcus neoformans (NRRL Y-1518), Candida tropicalis (RCMB 05239), Penicillium expansum (IMI 146655), Microsporum canis (RCMB 0834), and Trichophyton mentagrophytes (RCMB 0925) were used as the fungal strains. Ampicillin and gentamicin were used as reference antibacterial drugs and amphotericin B was used as the reference antifungal drug. The antimicrobial studies revealed that the tested compounds 6-8, 11, 12, and 14-16 showed the highest activities against the bacterial and fungal strains. The current study showed that some benzo[g]traizoloquinazolines displayed remarkable antimicrobial activity and could be used as template for further design of potent antimicrobial agent.

Antimicrobial Activity of Synthesized 2-Methylthiobenzo[g][1,2,4]- triazolo[1,5-a]quinazoline Derivatives

BACKGROUND The present study was carried out to evaluate the antimicrobial activity of a synthesized 2-methylthio-benzo[g][1,2,4]triazolo[1,5- a]quinazoline series. The compounds (1-21) were tested against a variety of Gram-positive bacterial species including Bacillus subtilis (RCMB 01001 69-3), Enterococcus faecalis (RCMB 0100154-2), Staphylococcus aureus (RCMB 0100183-9), Staphylococcus epidermidis (RCMB 0100183-9) and Streptococcus pyogenes (RCMB 0100172-5). In addition, Gram-negative bacteria were also tested including Pseudomonas aeruginosa (RCMB 0100243-5), Escherichia coli (RCMB 010052-6), Proteus mirabilis (RCMB 01002 54-2), Klebsiella oxytoca (RCMB 01002 83-4) and Enterobacter cloacae (RCMB 01002 64-5). Furthermore, their activities were screened against ten types of fungi i.e. Aspergillus fumigatus (RCMB 02568), Syncephalastrum racemosum (RCMB 05922), Geotricum candidum (RCMB 05097), Candida albicans (RCMB 05036), Aspergillus niger (RCMB 02724), Cryptococcus neoformans (RCMB 05642), Candida tropicalis (RCMBA 05239), Penicillium expansum (RCMB 01924), Microsporum canis (RCMB 0834) and Trichophyton mentagrophytes (RCMB 0925). METHODS Evaluation of antimicrobial activity was performed using agar well diffusion method in comparison with ampicillin and gentamycin as antibacterial reference drugs, and amphotericin B as antifungal reference drug. The minimum inhibitory concentration (MIC) was determined using the broth double dilution technique. RESULTS The MIC values of the tested compounds were reported in .g/mL in which ampicillin, gentamicin and amphotericin B were used as standard reference drugs. The obtained results revealed that compounds 3, 4, 7, 8, 9, 10, 11, 14, 17, 18, 19, 20 and 21 showed significant antimicrobial activity against six bacterial and six fungal strains. CONCLUSION The promising compounds could be employed as useful scaffolds for building of new derivatives with more potent antimicrobial effects.

Molecular modeling, enzyme activity, anti-inflammatory and antiarthritic activities of newly synthesized quinazoline derivatives

AIM 16 thioxoquinazolines were evaluated in vivo for anti-inflammatory activity using carrageenan-induced paw edema assay. RESULTS In particular, out of the targets (1-16), compounds 4 and 6 displayed the highest anti-inflammatory activity (≥80%) and furtherly tested against complete Freunds adjuvant-induced arthritic rats. Significant reduction in the serum level of IL-1β, COX-2 and prostaglandin E2 in the complete Freunds adjuvant rats is demonstrated by compounds 4 and 6. Furthermore, compound 4 showed non-selective activity against COX-1 and COX 2, however, compound 6 was specific toward COX-2. Molecular docking study has demonstrated the possible binding modes of the active quinazolines 4 and 6 in the COX-2 active site. CONCLUSION These targets could be used as templates for further development of new derivatives with potent anti-inflammatory activity.

Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study

Abstract A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b–9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b–9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC50 range of 7.7–14.2 µg/ml, in comparison with the reference drugs 5-fluorouracil (IC50 = 7.9 and 5.3 µg/ml, respectively) and afatinib (IC50 = 5.4 and 11.4 µg/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC50 values at micromolar levels (IC50 range of 16.01–1.11 µM) compared with the reference drugs sorafenib (IC50 = 1.14 µM) and erlotinib (IC50 = 0.1 µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase. Graphical Abstract

Screening and evaluation of antioxidant activity of some 1,2,4-triazolo[1,5-a]quinazoline derivatives

AIM The present study was carried out to assess a new series of triazoloquinazolines 1-40 for their antioxidant activities using 1,1-diphenyl-2-picryl hydrazyl radical scavenging, ferric reduction antioxidant power and reducing power capability assays. RESULTS All triazoloquinazolines 1-40 exhibited antioxidant activity ranged from weak to moderate and high. The obtained findings revealed that the triazoloquinazolines 30, 36 and 38-40 have superiority among all compounds, demonstrating the highest capacity to deplete 1,1-diphenyl-2-picryl hydrazyl and free radicals, in relation to butylated hydroxyl toluene, as a synthetic antioxidant agent. CONCLUSION Chemical modifications together with density functional theory study on the targets supplied us with some valuable clarifications about the required properties needed for the target compounds to be more active against free radicals.

Removal of antibiotics from water and waste milk by ozonation: kinetics, byproducts, and antimicrobial activity

The use of antibiotics in the dairy farming for curing and growth promotion results in the production of massive quantities of non-recyclable wastewater by the conventional purification techniques. Additionally, waste milk is produced during the drug withholding periods, which is not suitable for human or animal consumption and cause huge economic loss as well as present serious environmental waste. This study was designed to investigate the decomposition of various antibiotic compounds in un-buffered aqueous solutions and milk samples by ozonation process. Commonly administered broad-spectrum antibiotics such as amoxicillin, doxycycline, ciprofloxacin, and sulphadiazine were selected as model examples in the current investigation. Gradual exposure of these antibiotics to increasing ozone gas concentration induced increasing removal percentages of the antibiotics in spiked water and milk samples. The removal reached 95% across all the tested treated antibiotics with ozone dose as low as 75 mg L-1. It was noted that the removal of antibiotics in milk samples is more efficient with faster rate constants. This was attributed to the self-buffering characteristic of milk that maintains the neutral pH, keeping the amine groups un-protonated and more reactive towards the electrophilic attack by the molecular ozone. 1H NMR as well as HPLC experiments support the near complete removal of antibiotics and indicated the break down to simpler and more soluble fragments of acidic nature. Bacterial growth experiments, conducted with E. coli, and milk ageing experiments provided clear evidences that the resulting decomposition byproducts lack both toxicity effect and antimicrobial activity. This study provides a viable route to remove hazardous materials, which contribute to a growing issue of antibiotic resistance of pathogenic bacteria.

Advancing pharmaceuticals and patient safety in Saudi Arabia: A 2030 vision initiative

Low-quality medicines deliver sub-optimal clinical outcomes and waste precious health resources. It is important to ensure that public funds are spent on healthcare technologies that meet national regulatory bodies such as the Saudi Food and Drug Authority (SFDA), quality standards for safety, efficacy, and quality. Medicines quality is a complicated combination of pre-market regulatory specifications, appropriate sourcing of ingredients (active pharmaceutical ingredient (API), excipients, etc.), manufacturing processes, healthcare ecosystem communications, and regular and robust pharmacovigilance practices. A recent conference in Riyadh, sponsored by King Saud University, sought to discuss these issues and develop specific policy recommendations for the Saudi 2030 Vision plan. This and other efforts will require more and more creative educational programs for physicians, pharmacists, hospitals, and patients, and, most importantly evolving regulations on quality standards and oversight by Saudi health authorities.