Hamdy Abdel-Rahman - Academia.edu (original) (raw)

Papers by Hamdy Abdel-Rahman

Research paper thumbnail of Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

Archiv der Pharmazie, 2009

A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidin... more A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidinone / 2-azetidinone nucleus were synthesized by reacting N'-substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a-g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and (1)H-NMR). All the title compounds were tested for their in-vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv using Alamar-Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in microg/mL. Among the series, compounds 2b, 2g, 3b, and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.

Research paper thumbnail of Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels

BioMed Research International, 2017

We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of trama... more We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n=6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 μg·kg−1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils’ diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0–480 and ASC0–∞) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the en...

Research paper thumbnail of Design of β-Secretase (BACE1) Inhibitors with Carboxylic Acid Bioisosteres

Peptide science: proceedings of the... Japanese Peptide Symposium, Mar 1, 2006

Research paper thumbnail of Synthesis of 1,2,4-triazole derivatives and evaluation of their antioxidant activity

Journal of advanced Biomedical and Pharmaceutical Sciences, 2018

Research paper thumbnail of Synthesis, Antimicrobial and Molecular Modeling Studies of Some Benzophenone-based Thiazole and 4-Thiazolidinone Derivatives

Egyptian Journal of Chemistry, 2020

Research paper thumbnail of Lipases-catalyzed enantioselective kinetic resolution of alcohols

The purpose of this brief review is to report overviews of the state of art in the kinetic resolu... more The purpose of this brief review is to report overviews of the state of art in the kinetic resolution of racemic alcohols using lipases. This review includes types of lipases, function, and applications in organic synthesis, as well as their mechanism in hydrolysis of esters. Moreover the review highlight success stories about the separation of different alcohols racemates explaining the advantages of the methods employed. A particular attention was drawn to the literature published within the period from 2010 upwards to June 2015.

Research paper thumbnail of Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins

RSC Advances, 2020

Design of 2-phenylquinazolin-4(3H)one-trihydroxyphenyl Schiff base conjugates as COVID-19 therapy.

Research paper thumbnail of Synthesis, molecular docking and biological evaluation of 2,4 disubstituted quinazolines with multi-target activities as anti-cancer and antimicrobial agents

Egyptian Journal of Chemistry, 2020

A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-targe... more A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-target therapeutic agents that may act as anti-cancer and antimicrobial agents. The target compounds were evaluated for primary anti-cancer activity followed by EGFR inhibition assay for most potent compounds. Compounds 6 and 8c exhibited good EGFR inhibition activity with IC50 values of 0.201 and 0.405 µM, respectively, in comparison to lapatinib as a reference with IC50 value of 0.115 µM. Docking study of the synthesized compounds into the binding site of EGFR tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. Moreover, antimicrobial activity, cytotoxity and hemolytic analysis were estimated according to CO-ADD (The Community for Antimicrobial Drug Discovery) procedures. Compounds 4 and 5c possessed potent antifungal activity with minimum inhibitory concentration (MIC) values of 8 and 4 µg/mL against C. albicans and C. neoformance, respectively, compared to fluconazole as a reference drug with MIC values of 0.125 and 8 µg/mL against same fungi.

Research paper thumbnail of Novel Benzimidazole/Hydrazone Derivatives as Promising Anticancer Lead Compounds: Design, Synthesis, and Molecular Docking Study

Journal of advanced Biomedical and Pharmaceutical Sciences, 2020

A novel series of benzimidazole-hydrazone derivatives was designed and synthesized as a potential... more A novel series of benzimidazole-hydrazone derivatives was designed and synthesized as a potential anti-cancer agents. The structure of the target compounds was assured using different spectroscopic methods such as IR, 1 H NMR, 13 C NMR and elemental analysis. These new compounds were examined and evaluated for their antiproliferative activities against 60 different cell lines. Combination of benzimidazole scaffold with hydrazone group exhibited promising anti-cancer activity. Compounds 3a and 3b showed significant activity against different cancer cells lines between 50-84 % of growth inhibition. A molecular modeling study for compounds 3a and 3b into VEGFR-2 active site was performed with reasonable docking scores.

Research paper thumbnail of Saccharomonosporine A inspiration; synthesis of potent analogues as potential PIM kinase inhibitors

RSC Advances, 2020

The E isomer of compound 5 exhibited a potent inhibitory effect against PIM kinase isoforms of IC... more The E isomer of compound 5 exhibited a potent inhibitory effect against PIM kinase isoforms of IC50s 0.30–0.41 μM.

Research paper thumbnail of Allophenylnorstatine-Containing HIV-1 Protease Inhibitors: Design, Synthesis and Structure-Activity Relationships for Selected P2 Ligands

Bulletin of Pharmaceutical Sciences. Assiut, 2005

The design and development of potent HIV protease inhibitors remain an attractive target for anti... more The design and development of potent HIV protease inhibitors remain an attractive target for antiviral therapy. A novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic have been reported. In this work we fixed P 2` (as tert-butylamino or 2-methylbenzylamino) and changed P 2 moiety to provide two series of dipeptide analogs. Preliminary evaluation of the activity of the synthesized derivatives were determined as percentage of enzyme inhibition at 5 M level. The results showed that the introduction of 2-methylbenzylamino moiety as P 2` ligand 6a-e considerably improved HIV inhibitory activity in comparison with the tert-butyl amino analogs 5a-e. It was found that compounds in both series retained activity still less than the lead compounds KNI-577 and KNI-727.

Research paper thumbnail of Novel 1,2,4-TRIAZOLE-3-MERCAPTOACETIC Acid Derivatives as Potential Antimycobacterial and Antimicrobial Agents

Bulletin of Pharmaceutical Sciences. Assiut, 2006

Research paper thumbnail of Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors

European journal of medicinal chemistry, Jan 5, 2018

A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for thei... more A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for their antiproliferative activities against NCI 60 cell line. Compounds 10 (a, c), 11 (a-d), and 14 (a-e) were selected for evaluation at single concentration of 10 μM towards panel of sixty cancer cell lines. Some of nitric oxide (NO) donating triazole/oxime hybrids 11a-d showed antiproliferative activity better than their corresponding ketones. On the other hand, the thiazolo [3,2-b][1,2,4]-triazoles 14a-e showed remarkable antiproliferative activities against the same cell lines. Compound 14d was selected for five dose testing against the full panel of 60 human tumor cell lines. Compound 14d showed high selectivity against renal subpanel with selectivity ratio of 6.99 at GI level. Compounds 11a-d, 10a-d and 14a-e were tested against four cell lines using MTT assay then compounds of the least IC were evaluated against three known anticancer targets including EGFR, BRAF and Tubulin. The resu...

Research paper thumbnail of Novel 1,2,4-triazole derivatives as potential anticancer agents: Design, synthesis, molecular docking and mechanistic studies

Bioorganic chemistry, Feb 5, 2017

A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for th... more A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition with IC50 = 3.6 μM. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.

Research paper thumbnail of Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Bioorganic & medicinal chemistry, 2018

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substr... more Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to seri...

Research paper thumbnail of Stability-Indicating UPLC and TLC-Densitometric Methods for Determination of Benztropine Mesylate and Its Carcinogenic Degradation Product

Journal of Chromatographic Science, 2017

Two accurate, precise and highly selective stability-indicating methods were adopted for simultan... more Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degradation product, benzophenone (BPH) either in pure form or in the pharmaceutical formulation without any preliminary separation steps. The first method is a thin layer chromatography (TLC)-densitometric method that depended on separation of BNZ from its degradate on TLC aluminum plates precoated with silica gel 60 F 254 as the stationary phase using a developing system consisted of hexane:methylene chloride:triethylamine (5:5:0.6, by volume) and scanning the separated bands at 235 nm. Linear regression analysis data for the calibration plots of BNZ and BPH showed perfect linear relationships over the concentration range of 1.5-10 and 1-10 μg band −1 , respectively. The second method is (UPLC) method, at which the mixture was separated on a reversed phase C8 analytical column (1.9 μm ps, 50 mm × 2.1 i.d.) using a mobile phase of acetonitrile: aqueous sodium dodecyl sulfate (50:50, v/v) Adjusted to pH = 3 with phosphoric acid, at a flow rate of 0.5 mL min −1. Quantification was achieved at 210 nm based on peak area and linear calibration curves over the concentration ranges of (20-200 μg mL −1) and (5-50 μg mL −1) for BNZ and BPH, respectively, were obtained. The investigated methods were successfully applied to available dosage form and method validation has been carried out. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by reported one and no significant differences were obtained regarding both accuracy and precision.

Research paper thumbnail of Lipophilicity estimation of statins as a decisive physicochemical parameter for their hepato-selectivity using reversed-phase thin layer chromatography

Journal of pharmaceutical and biomedical analysis, Jan 5, 2017

Lipophilicity plays a crucial role in determining the hepato-selectivity and hence, the biologica... more Lipophilicity plays a crucial role in determining the hepato-selectivity and hence, the biological activity and the associated side effects of statins. Herein, the employment of RP-TLC for estimation of lipophilicity of six statins namely; atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin and fluvastatin is examined. A very good correlation between the chromatographically-determined retention parameters (relative lipophilicity (RM0) or lipophilic parameter (C0)) and both experimental and computed log P values were obtained. However, the results indicate that the type of organic modifier in the mobile phase system (methanol, acetonitrile and acetone) has a small influence on RM0 or C0 values. Higher values of RM0 or C0 are ascribed to lipophilic statins and lower values of RM0 or C0 are attributed to hydrophilic ones. Therefore, RM0 or C0 could be effectively used as simple practical predictors of extra-hepatic distributions of statins and thus their expected side effe...

Research paper thumbnail of Design and Synthesis of Substituted Pyridazinone-1-Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors

Archiv der Pharmazie, Jan 20, 2015

A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit p... more A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.

Research paper thumbnail of Synthesis and Evaluation of Quinazoline Amino Acid Derivatives as Mono Amine Oxidase (MAO) Inhibitors

Bioorganic & Medicinal Chemistry, 2015

A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared ... more A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC50=3.6×10(-9), 2.8×10(-9), 2.1×10(-9) M, respectively) comparable to that of the standard clorgyline (IC50=2.9×10(-9)M). 2-(2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohydrazide 15 showed selective MAO-A inhibition activity (SI=39524) superior to that of the standard clorgyline (SI=33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity.

Research paper thumbnail of DESIGN AND SYNTHESIS OF HIGHLY POTENT CELL-PERMEABLE PEPTIDOMIMETIC INHIBITORS OF ALZHEIMER'S beta-SECRETASE (BACE1)

Research paper thumbnail of Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

Archiv der Pharmazie, 2009

A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidin... more A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidinone / 2-azetidinone nucleus were synthesized by reacting N'-substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a-g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and (1)H-NMR). All the title compounds were tested for their in-vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv using Alamar-Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in microg/mL. Among the series, compounds 2b, 2g, 3b, and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.

Research paper thumbnail of Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels

BioMed Research International, 2017

We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of trama... more We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n=6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 μg·kg−1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils’ diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0–480 and ASC0–∞) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the en...

Research paper thumbnail of Design of β-Secretase (BACE1) Inhibitors with Carboxylic Acid Bioisosteres

Peptide science: proceedings of the... Japanese Peptide Symposium, Mar 1, 2006

Research paper thumbnail of Synthesis of 1,2,4-triazole derivatives and evaluation of their antioxidant activity

Journal of advanced Biomedical and Pharmaceutical Sciences, 2018

Research paper thumbnail of Synthesis, Antimicrobial and Molecular Modeling Studies of Some Benzophenone-based Thiazole and 4-Thiazolidinone Derivatives

Egyptian Journal of Chemistry, 2020

Research paper thumbnail of Lipases-catalyzed enantioselective kinetic resolution of alcohols

The purpose of this brief review is to report overviews of the state of art in the kinetic resolu... more The purpose of this brief review is to report overviews of the state of art in the kinetic resolution of racemic alcohols using lipases. This review includes types of lipases, function, and applications in organic synthesis, as well as their mechanism in hydrolysis of esters. Moreover the review highlight success stories about the separation of different alcohols racemates explaining the advantages of the methods employed. A particular attention was drawn to the literature published within the period from 2010 upwards to June 2015.

Research paper thumbnail of Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins

RSC Advances, 2020

Design of 2-phenylquinazolin-4(3H)one-trihydroxyphenyl Schiff base conjugates as COVID-19 therapy.

Research paper thumbnail of Synthesis, molecular docking and biological evaluation of 2,4 disubstituted quinazolines with multi-target activities as anti-cancer and antimicrobial agents

Egyptian Journal of Chemistry, 2020

A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-targe... more A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-target therapeutic agents that may act as anti-cancer and antimicrobial agents. The target compounds were evaluated for primary anti-cancer activity followed by EGFR inhibition assay for most potent compounds. Compounds 6 and 8c exhibited good EGFR inhibition activity with IC50 values of 0.201 and 0.405 µM, respectively, in comparison to lapatinib as a reference with IC50 value of 0.115 µM. Docking study of the synthesized compounds into the binding site of EGFR tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. Moreover, antimicrobial activity, cytotoxity and hemolytic analysis were estimated according to CO-ADD (The Community for Antimicrobial Drug Discovery) procedures. Compounds 4 and 5c possessed potent antifungal activity with minimum inhibitory concentration (MIC) values of 8 and 4 µg/mL against C. albicans and C. neoformance, respectively, compared to fluconazole as a reference drug with MIC values of 0.125 and 8 µg/mL against same fungi.

Research paper thumbnail of Novel Benzimidazole/Hydrazone Derivatives as Promising Anticancer Lead Compounds: Design, Synthesis, and Molecular Docking Study

Journal of advanced Biomedical and Pharmaceutical Sciences, 2020

A novel series of benzimidazole-hydrazone derivatives was designed and synthesized as a potential... more A novel series of benzimidazole-hydrazone derivatives was designed and synthesized as a potential anti-cancer agents. The structure of the target compounds was assured using different spectroscopic methods such as IR, 1 H NMR, 13 C NMR and elemental analysis. These new compounds were examined and evaluated for their antiproliferative activities against 60 different cell lines. Combination of benzimidazole scaffold with hydrazone group exhibited promising anti-cancer activity. Compounds 3a and 3b showed significant activity against different cancer cells lines between 50-84 % of growth inhibition. A molecular modeling study for compounds 3a and 3b into VEGFR-2 active site was performed with reasonable docking scores.

Research paper thumbnail of Saccharomonosporine A inspiration; synthesis of potent analogues as potential PIM kinase inhibitors

RSC Advances, 2020

The E isomer of compound 5 exhibited a potent inhibitory effect against PIM kinase isoforms of IC... more The E isomer of compound 5 exhibited a potent inhibitory effect against PIM kinase isoforms of IC50s 0.30–0.41 μM.

Research paper thumbnail of Allophenylnorstatine-Containing HIV-1 Protease Inhibitors: Design, Synthesis and Structure-Activity Relationships for Selected P2 Ligands

Bulletin of Pharmaceutical Sciences. Assiut, 2005

The design and development of potent HIV protease inhibitors remain an attractive target for anti... more The design and development of potent HIV protease inhibitors remain an attractive target for antiviral therapy. A novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic have been reported. In this work we fixed P 2` (as tert-butylamino or 2-methylbenzylamino) and changed P 2 moiety to provide two series of dipeptide analogs. Preliminary evaluation of the activity of the synthesized derivatives were determined as percentage of enzyme inhibition at 5 M level. The results showed that the introduction of 2-methylbenzylamino moiety as P 2` ligand 6a-e considerably improved HIV inhibitory activity in comparison with the tert-butyl amino analogs 5a-e. It was found that compounds in both series retained activity still less than the lead compounds KNI-577 and KNI-727.

Research paper thumbnail of Novel 1,2,4-TRIAZOLE-3-MERCAPTOACETIC Acid Derivatives as Potential Antimycobacterial and Antimicrobial Agents

Bulletin of Pharmaceutical Sciences. Assiut, 2006

Research paper thumbnail of Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors

European journal of medicinal chemistry, Jan 5, 2018

A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for thei... more A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for their antiproliferative activities against NCI 60 cell line. Compounds 10 (a, c), 11 (a-d), and 14 (a-e) were selected for evaluation at single concentration of 10 μM towards panel of sixty cancer cell lines. Some of nitric oxide (NO) donating triazole/oxime hybrids 11a-d showed antiproliferative activity better than their corresponding ketones. On the other hand, the thiazolo [3,2-b][1,2,4]-triazoles 14a-e showed remarkable antiproliferative activities against the same cell lines. Compound 14d was selected for five dose testing against the full panel of 60 human tumor cell lines. Compound 14d showed high selectivity against renal subpanel with selectivity ratio of 6.99 at GI level. Compounds 11a-d, 10a-d and 14a-e were tested against four cell lines using MTT assay then compounds of the least IC were evaluated against three known anticancer targets including EGFR, BRAF and Tubulin. The resu...

Research paper thumbnail of Novel 1,2,4-triazole derivatives as potential anticancer agents: Design, synthesis, molecular docking and mechanistic studies

Bioorganic chemistry, Feb 5, 2017

A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for th... more A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition with IC50 = 3.6 μM. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.

Research paper thumbnail of Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Bioorganic & medicinal chemistry, 2018

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substr... more Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to seri...

Research paper thumbnail of Stability-Indicating UPLC and TLC-Densitometric Methods for Determination of Benztropine Mesylate and Its Carcinogenic Degradation Product

Journal of Chromatographic Science, 2017

Two accurate, precise and highly selective stability-indicating methods were adopted for simultan... more Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degradation product, benzophenone (BPH) either in pure form or in the pharmaceutical formulation without any preliminary separation steps. The first method is a thin layer chromatography (TLC)-densitometric method that depended on separation of BNZ from its degradate on TLC aluminum plates precoated with silica gel 60 F 254 as the stationary phase using a developing system consisted of hexane:methylene chloride:triethylamine (5:5:0.6, by volume) and scanning the separated bands at 235 nm. Linear regression analysis data for the calibration plots of BNZ and BPH showed perfect linear relationships over the concentration range of 1.5-10 and 1-10 μg band −1 , respectively. The second method is (UPLC) method, at which the mixture was separated on a reversed phase C8 analytical column (1.9 μm ps, 50 mm × 2.1 i.d.) using a mobile phase of acetonitrile: aqueous sodium dodecyl sulfate (50:50, v/v) Adjusted to pH = 3 with phosphoric acid, at a flow rate of 0.5 mL min −1. Quantification was achieved at 210 nm based on peak area and linear calibration curves over the concentration ranges of (20-200 μg mL −1) and (5-50 μg mL −1) for BNZ and BPH, respectively, were obtained. The investigated methods were successfully applied to available dosage form and method validation has been carried out. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by reported one and no significant differences were obtained regarding both accuracy and precision.

Research paper thumbnail of Lipophilicity estimation of statins as a decisive physicochemical parameter for their hepato-selectivity using reversed-phase thin layer chromatography

Journal of pharmaceutical and biomedical analysis, Jan 5, 2017

Lipophilicity plays a crucial role in determining the hepato-selectivity and hence, the biologica... more Lipophilicity plays a crucial role in determining the hepato-selectivity and hence, the biological activity and the associated side effects of statins. Herein, the employment of RP-TLC for estimation of lipophilicity of six statins namely; atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin and fluvastatin is examined. A very good correlation between the chromatographically-determined retention parameters (relative lipophilicity (RM0) or lipophilic parameter (C0)) and both experimental and computed log P values were obtained. However, the results indicate that the type of organic modifier in the mobile phase system (methanol, acetonitrile and acetone) has a small influence on RM0 or C0 values. Higher values of RM0 or C0 are ascribed to lipophilic statins and lower values of RM0 or C0 are attributed to hydrophilic ones. Therefore, RM0 or C0 could be effectively used as simple practical predictors of extra-hepatic distributions of statins and thus their expected side effe...

Research paper thumbnail of Design and Synthesis of Substituted Pyridazinone-1-Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors

Archiv der Pharmazie, Jan 20, 2015

A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit p... more A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.

Research paper thumbnail of Synthesis and Evaluation of Quinazoline Amino Acid Derivatives as Mono Amine Oxidase (MAO) Inhibitors

Bioorganic & Medicinal Chemistry, 2015

A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared ... more A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC50=3.6×10(-9), 2.8×10(-9), 2.1×10(-9) M, respectively) comparable to that of the standard clorgyline (IC50=2.9×10(-9)M). 2-(2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohydrazide 15 showed selective MAO-A inhibition activity (SI=39524) superior to that of the standard clorgyline (SI=33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity.

Research paper thumbnail of DESIGN AND SYNTHESIS OF HIGHLY POTENT CELL-PERMEABLE PEPTIDOMIMETIC INHIBITORS OF ALZHEIMER'S beta-SECRETASE (BACE1)