Marwa M. Abdel-Aziz

Quaternized N-substituted carboxymethyl chitosan derivatives as antimicrobial agents

Introduction of quaternary ammonium moieties into N-substituted carboxymethyl chitosan (N-substituted CMCh) derivatives enhances their biological activity. Several derivatives of CMCh having a variety of N-aryl substituents bearing either electron-donating or electron withdrawing groups have been synthesized by the reaction between amino group of CMCh with various aromatic aldehydes under acidic conditions, followed by reduction of the produced Schiff base derivatives with sodium cyanoborohydride. Each of the reduced derivatives was further quaternized using N-(3-chloro-2-hydroxy-propyl)trimethylammonium chloride (Quat-188). The resulting quaternized materials were characterized by FTIR and (1)H NMR spectroscopy. Their antibacterial activities against Streptococcus pneumoniae (S. pneumonia, RCMB 010010), Bacillis subtilis (B. subtilis, RCMB 010067), as Gram positive bacteria and against Escherichia coli (E. coli, RCMB 010052) as Gram negative bacteria and their antifungal activities against Aspergillus fumigatus (A. fumigates, RCMB 02568), Geotricum candidum (G. candidum, RCMB 05097), and Candida albicans (C. albicans, RCMB 05031) were examined using agar disk diffusion method. The results indicated that all the quaternized derivatives showed better antimicrobial activities than that of CMCh. These derivatives are highly potent against Gram positive bacteria compared to Gram negative bacteria. This is illustrated for example as the values of minimum inhibitory concentration (MIC) of Q4NO2-BzCMCh against B. subtilis and S. pneumonia were 6.25 and 12.5 μg/mL, respectively corresponded to 20.0 μg/mL against E. coli. The antimicrobial activity of quaternized N-aryl CMCh derivatives affected by not only the nature of the microorganisms but also by the nature, position and number of the substituent groups on the phenyl ring. Thus while the derivatives with groups of electron withdrawing nature show higher inhibition zone diameter and lower MIC values relative to that of those having electron-donating nature, the non-substituted derivative lies between these two extremes. Antibacterial activities of Q4NO2-BzCMCh, Q3Cl-BzCMCh and Q3Br-BzCMCh against E. coli are nearly equivalent to that of the standard drug Gentamycin. Q3Br-BzCMCh emerged almost equivalent antibacterial activity to Ampicillin against S. pneumonia.

Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides

Three series of 6-aryl-2-methylnicotinohydrazides 4a–i, N′-arylidene-6-(4-bromophenyl)-2-methylnicotino hydrazides 7a–f, and N′-(un/substituted 2-oxoindolin-3-ylidene)-6-(4-fluorophenyl)-2-methylnicotinohydrazides 8a–c were synthesized and evaluated for their potential in vitro antimycobacterial activity against M. tuberculosis. The results showed that isatin hydrazides 8a–c are remarkably more active than the parent hydrazide 4c. Hydrazides 8b and 8c exhibited the highest activity among all the tested compounds (MIC = 12.5 and 6.25 µg/mL, respectively). Compounds 8b and 8c were also devoid of apparent cytotoxicity to HT-29, PC-3, A549, HepG2 and MCF-7 cancer cell lines. Besides, 8b and 8c showed good drug-likeness scores of 0.62 and 0.41, respectively. Those two isatin hydrazides could offer an excellent framework for future development to obtain more potent antitubercular agents. The SAR study suggested that lipophilicity of the synthesized derivatives is a crucial element that accounts for their antimycobacterial activity. Finally, a theoretical kinetic study was established to predict the ADME of the active derivatives.

Synthesis, Biological Evaluation and Molecular Docking of Certain Sulfones as Potential Nonazole Antifungal Agents.

We reported herein the synthesis, antifungal activity, docking and in silico ADME prediction studies of four novel series of sulfones 6a–f, 8a–c, 10a–f and 12a–c. All the newly synthesized sulfones were tested against four strains of Candida (including fluconazole-resistant Candida), two strains of Aspergillus, two dermatophytic fungi (Trichophytons mentagrophyte and Microsporum canis) and Syncephalastrum sp. with fluconazole as a reference drug. In general, compounds 8a and 10b showed selective and potent anticandidal activity (MIC: 0.19–0.81 µM) relative to fluconazole (MIC = 1.00 µM). Furthermore, 10e and 12a elicited a remarkable and selective antifungal activity against Aspergillus sp. and the dermatophytic fungi (MIC: 0.16–0.79 µM) relative to fluconazole (MIC: 2–2.6 µM). Moreover, the docking results of the sulfones 6a, 8a, 10a and 10b at the active site of CYT P450 14α-sterol demethylase showed a comparable binding interaction (interaction Energy = −34.87 to −42.43 kcal/mol) with that of fluconazole (IE = −40.37 kcal/mol).

Synthesis, Biological Evaluation and 2D-QSAR Study of Halophenyl Bis-Hydrazones as Antimicrobial and Antitubercular Agents

In continuation of our endeavor towards the development of potent and effective antimicrobial agents, three series of halophenyl bis-hydrazones (14a–n, 16a–d, 17a and 17b) were synthesized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the identification of five molecules 14c, 14g, 16b, 17a and 17b (MIC range from 0.12 to 7.81 μg/mL) with broad antimicrobial activity against Mycobacterium tuberculosis; Aspergillus fumigates; Gram positive bacteria, Staphylococcus aureus, Streptococcus pneumonia, and Bacillis subtilis; and Gram negative bacteria, Salmonella typhimurium, Klebsiella pneumonia, and Escherichia coli. Three of the most active compounds, 16b, 17a and 17b, were also devoid of apparent cytotoxicity to lung cancer cell line A549. Amphotericin B and ciprofloxacin were used as references for antifungal and antibacterial screening, while isoniazid and pyrazinamide were used as references for antimycobacterial activity. Furthermore, three Quantitative Structure Activity Relationship (QSAR) models were built to explore the structural requirements controlling the different activities of the prepared bis-hydrazones.

Synthesis, in Vitro and in Silico Studies of Some Novel 5-Nitrofuran-2-yl Hydrazones as Antimicrobial and Antitubercular Agents

In this study, we synthesized two series of novel 5-nitrofuran-2-carbohydrazides 21a-h and 22a-e in addition to a third series of thiophene-2-carbohydrazides 23a-g to develop potent antimicrobial and/or antitubercular agents. The newly synthesized compounds were evaluated in vitro for their antimicrobial and antimycobacterial activities. Most of the 5-nitrofuran-2-carbohydrazides 21a-h and 22a-e displayed variable activity against Aspergillus fumigates, Staphylococcus aureus, Streptococcus pneumonia, Bacillis subtilis, Salmonella typhimurium, Klebsiella pneumonia, Escherichia coli and Mycobacterium tuberculosis. The sulfonamide derivative 21f exhibited superior potency and broad-spectrum antimicrobial activity with minimum inhibitory concentration (MIC)=0.06-0.98 µg/mL and antimycobacterial activity with MIC=3.9 µg/mL. The 5-nitrofuran-2-carbohydrazides 21a, b, g, h and 22a-c exhibited significant antibacterial activity with MIC values in the range of 0.12-7.81 µg/mL. The significances of the 5-nitrofuran moiety and sulfonamide function were explored via the structure-activity relationship (SAR) study. In addition, docking studies revealed that the p-amino benzoic acid (PABA) and binding pockets of the dihydropteroate synthase (DHPS) were successfully occupied by compound 21f. Furthermore, two quantitative structure-activity relationship (QSAR) models were built to explore the structural requirements which controlled the activity.

Novel 6-Phenylnicotinohydrazide Derivatives: Design, Synthesis and Biological Evaluation as a Novel Class of Antitubercular and Antimicrobial Agents

In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydrazide, herein we report the design, synthesis and biological evaluation of three sets of 6-phenylnicotinohydrazide derivatives 8a-g, 12 and 16a, b. The designed compounds were synthesized and in vitro evaluated for their antitubercular activity. In addition, their antifungal and antibacterial activities were evaluated as well. The nicotinohydrazide class displayed different levels of antimicrobial activity and possessed a distinctive pattern of selectivity against the tested microorganisms. However, the 2,6-dichlorobenzylidene counterpart 8b emerged as the most active one in this study, with superior antimycobacterial activity (minimum inhibitory concentration (MIC)=3.90 µg/mL) and potent broad-spectrum antimicrobial activities with MIC range of 0.24-1.95 µg/mL. The structure-activity relationship for such nicotinohydrazides has been established. Further, the cytotoxicity of the most active antitubercular compounds 8b, d and g were tested against the normal breast cells WI-38; none of them displayed significant cytotoxic effect, thereby providing a good therapeutic index.

An improved synthesis of pyrido[2,3-d]pyrimidin-4(1H)-ones and their antimicrobial activity

The screening of a small library of diverse chemical structures resulted in the identification of 2-thioxodihydropyrido[2,3-d]pyrimidine 10a as having broad spectrum antibacterial activity (MIC 0.49-3.9 μg mL-1), and reasonable antifungal activity (MIC 31.25 μg mL-1). An expeditious synthesis of 10a was optimized by varying solvents, catalysts and the use of microwave irradiation with the best conditions using DMF as a solvent, I2 (10 mol%) and a 30 minutes reaction time compared to 15 h for classic conventional heating. The pharmacokinetic properties and calculation of drug likeness of 10a suggested good traditional drug-like properties and led to the synthesis of a small library with seven compounds 10a and 10d-i showing broad antimicrobial activity (MIC = 0.49-7.81 μg mL-1) and selectivity indices of more than 5.6 against the normal colon cell line (CCD-33Co). The antifungal activity of compounds 10d-i was moderate to strong with MIC values of 1.95-15.63 μg mL-1.

Green synthesis of antimicrobial and antitumor N , N , N -trimethyl chitosan chloride/poly (acrylic acid)/silver nanocomposites

The present study is imported to solve two critical problems we face in our daily life which are microbial pollution and colon cancer. One pot green synthesis of a water soluble polyelectrolyte complex (PEC) between cationic polysaccharide as N,N,N-trimethyl chitosan chloride (TMC) and anionic polymer as poly (acrylic acid) (PAA) in presence of silver nanoparticles to yield (TMC/PAA/Ag) nanocomposites with different Ag weight ratios. Structure of TMC, PAA and TMC/PAA (PEC) were proved via different analysis tools. TMC/PAA and its Ag nanocomposites are used as antimicrobial agents against different pathogenic bacteria and fungi to solve microbial pollution. TMC/PAA-Silver nanocomposites had the highest antimicrobial activity which increases with increasing Ag %. Cytotoxicity data confirmed also that TMC/PAA/Ag (3%) had the most cytotoxic effect (the less cell viability %) towards colon cancer. TMC/PAA (PEC) was formed through electrostatic interactions between N-quaternized (-N+R3) groups in TMC and carboxylate (-COO-) groups in PAA.

Larvicidal potential of irradiated myco-insecticide from Metarhizium anisopliae and larvicidal synergistic effect with its mycosynthesized titanium nanoparticles (TiNPs)

Abstract This work was undertaken to investigate the effect of different dose levels of gamma irradiation ranged from 0.2 to 1kGy on Metarhizium anisopliae lipase, protease, amylase and nitrate reductase activities. The optimum results obtained with a dose level 0.4kGy which stimulated the maximum enzymatic activities. Titanium nanoparticles (TiNPs) were mycosynthesized using unirradiated and irradiated (0.4KGy)M. anisopliae and characterized using UV–Vis spectrophotometry, electron microscopy (TEM) and energy-dispersive spectrometry (EDX). In addition, the difference between the growing of unirradiated and irradiated M. anisopliae on larval cuticle was studied using scanning electron microscopy. In Insecticidal activity of unirradiated and irradiated M. anisopliae with and without their mycosynthesized TiNPs were also examined against Galleria mellonella larvae and the highest larvicidal activity was obtained from the combination of irradiated M. anisopliae with its mycosynthesized TiNPs and that may be due to the higher fungal enzymatic activities, higher TiNPs concentration and lower TiNPs size. The synergistic studies revealed that there is a synergistic larvicidal relationship between irradiated M. anisopliae cells and their mycosynthesized TiNPs with a synergistic factor (SF) of 1.6 and 4.2 for LC50 and LC90, respectively. This study provided the first report of the synergistic effect between irradiated M. anisopliae and their mycosynthesized TiNPs. Such a combination could represent an effective approach for reducing the likelihood of increased insect resistance to entomopathogenic fungi.

Control of imipenem resistant-Klebsiella pneumoniae pulmonary infection by oral treatment using a combination of mycosynthesized Ag-nanoparticles and imipenem

Abstract Klebsiella pneumoniae (Kp) a common cause of pneumonia leads to intense lung injury and mortality that are correlated with infective exacerbations. A significant increase in the prevalence of imipenem resistant K. pneumoniae (IRKP) has been observed in common human pathogens. The rapid emergence of IRKP has limited the availability of anti-bacterial treatment options. Silver nano-particles (AgNPs) are one of the well-known antibacterial substances showing such multimode antibacterial action. Therefore, AgNPs are suitable candidates for use in combinations with imipenem in order to improve its antibacterial action. Fifteen fungal species were screened for mycosynthesis of silver nanoparticles (AgNPs), only eight fungal species were found to reduce the silver salt into silver nanoparticles which was characterized by UV–visible spectrophotometric analysis, Energy Dispersive Analysis of X-ray (EDX) and transmission electron microscopy. Consistent with characterized silver nanoparticles, mycosynthesized AgNPs by Verticillium albo-atrum (RCMB 039001) was found the higher in concentration (as detected by UV–visible spectrophotometric analysis) and the least in size (as detected by TEM analysis) so, it was chosen for further studies such as in vitro antibacterial activity against Imipenem resistant K. pneumonia (IRKP), MIC, FIC measurements and in vivo study. In this work a strong synergistic antibacterial effect between AgNPs and imipenem was detected in vitro (with FIC Index 0.07) and in vivo against IRKP strain. These results suggested that sliver nanoparticles have an effective antibacterial action on bacterial count, histopathology as well as protective immune response in an IRKP rat model.