Reem Arafa - Academia.edu (original) (raw)
Papers by Reem Arafa
Medicinal Chemistry Research, 2011
The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5... more The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5-b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for carbonic anhydrase (CA) inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 11 and 12 exhibited better activities than the reference drug doxorubicin (IC50 = 71.8 μM) with IC50 values of 52.6 μM and 67.3 μM, respectively. On the other hand, compounds 6, 10, and 13 showed IC50 values (71.8 μM, 69.8 μM, and 70.8 μM, respectively) comparable to that of the reference drug doxorubicin. In addition, docking of the synthesized compounds into human carbonic anhydrase isozyme II (hCA II) active site was performed in order to predict the affinity and the orientation of these compounds at the isozyme active site. Also, the most active compounds, 11 and 12, were selected and evaluated for their ability to enhance the cell killing effect of γ-radiation.
![Research paper thumbnail of In vitro anticancer screening and radiosensitizing evaluation of some new quinolines and pyrimido[4,5- b]quinolines bearing a sulfonamide moiety](https://attachments.academia-assets.com/50019815/thumbnails/1.jpg)
](European Journal of Medicinal Chemistry, 2010
Sulfonamide bearing compounds posses many types of biological activities and have recently been r... more Sulfonamide bearing compounds posses many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of twenty novel quinoline and pyrimido[4,5-b] quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for CA inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 6, 9 and 18 showed IC 50 values (72.9 mM, 72.1 mM and 71.9 mM, respectively) comparable to that of the reference drug doxorubicin (IC 50 ¼ 71.8 mM). On the other hand, compound 8 exhibited better activity than doxorubicin with an IC 50 value of 64.5 mM. Additionally, the most potent compounds 8 and 18 were evaluated for their ability to enhance the cell killing effect of g-radiation.
European Journal of Medicinal Chemistry, 2011
A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guani... more A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guanidines 7a,b and 8a,b as well as bis-imidamides 9–12a,b having a 1,3- or 1,4-diphenoxybenzene scaffold backbone were synthesized. The in vitro activity of the novel dications as antiprotozoal agents against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.) was assessed. Interestingly, six of the newly synthesized dications viz3a,b, 7a,b and 8a,b were more active against P.f. than the reference drug pentamidine. Also, some of the dications showed moderate antitrypanosomal activity. Thermal melting analysis of the novel dications was performed to determine their ligand-DNA relative binding affinities. Finally, docking of the dications with an AT rich DNA oligonucleotide was executed to understand their binding mode with the minor groove.Overlay of 7b (green) and pentamidine (red) showing their 2D binding interaction to the minor groove of the polydA.polydT DNA oligomer.► Novel dicationic flexible triaryl guanidines and imidamides were synthesized. ► All the dications were tested against T.b.r. and P.f. and compared to pentamidine. ► The guanidiniums and imidamides displayed good in vitro antiplasmodial activity. ► Tm data and docking showed these dications to bind as monocations to DNA.
Experimental Parasitology, 2011
Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affe... more Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT-rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD 50 values, good selectivity index, and good activity at 4°C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection.
Journal of The American Chemical Society, 2007
To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic ... more To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system while in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site show that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogs.
Journal of Chemical Education, 2006
ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-s... more ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-step synthesis and definitive characterization of a 3,5-diarylisoxazole via the chalcone and the chalcone dibromide is described. As each student prepares a differently substituted chalcone, and thus isoxazole, the project is individualized with regard to compound purification, characterization, and literature searches. To determine which isoxazole isomer was obtained from the synthesis, students compare their experimental 13C NMR data for C4 of the isoxazole to that predicted for each isomer. The predicted values are calculated using a formula that utilizes Hammett constants for estimating substituent NMR-shift effects on C4. Isomer determination can also be accomplished through interpretation of the fragmentation pattern observed in the mass spectrum. Keywords (Audience): Second-Year Undergraduate
Veterinary Parasitology, 2010
Biochemistry, 2005
The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades,... more The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades, this anti-trypanosomal agent has been known to intercalate into nucleic acids, with little preference for particular sequences. Only polydA-polydT tracts are relatively refractory to ethidium intercalation. In an effort to tune the sequence selectivity of known DNA binding agents, we report here the synthesis and detailed characterization of the mode of binding to DNA of a novel ethidium derivative possessing two guanidinium groups at positions 3 and 8. This compound, DB950, binds to DNA much more tightly than ethidium and exhibits distinct DNA-dependent absorption and fluorescence properties. The study of the mode of binding to DNA by means of circular and electric linear dichroism revealed that, unlike ethidium, DB950 forms minor groove complexes with AT sequences. Accurate quantification of binding affinities by surface plasmon resonance using A n T n hairpin oligomer indicated that the interaction of DB950 is over 10-50 times stronger than that of ethidium and comparable to that of the known minor groove binder furamidine. DB950 interacts weakly with GC sites by intercalation. DNase I footprinting experiments performed with different DNA fragments established that DB950 presents a pronounced selectivity for AT-rich sites, identical with that of furamidine. The replacement of the amino groups of ethidium with guanidinium groups has resulted in a marked gain of both affinity and sequence selectivity. DB950 provides protection against DNase I cleavage at AT-containing sites which frequently correspond to regions of enhanced cleavage in the presence of ethidium. Although DB950 maintains a planar phenanthridinium chromophore, the compound no longer intercalates at AT sites. The guanidinium groups of DB950, just like the amidinium group of furamidine (DB75), are the critical determinants for recognition of AT binding sites in DNA. The chemical modulation of the ethidium exocyclic amines is a profitable option to tune the nucleic acid recognition properties of phenylphenanthridinium dyes.
Journal of Chemical Education, 2006
ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-s... more ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-step synthesis and definitive characterization of a 3,5-diarylisoxazole via the chalcone and the chalcone dibromide is described. As each student prepares a differently substituted chalcone, and thus isoxazole, the project is individualized with regard to compound purification, characterization, and literature searches. To determine which isoxazole isomer was obtained from the synthesis, students compare their experimental 13C NMR data for C4 of the isoxazole to that predicted for each isomer. The predicted values are calculated using a formula that utilizes Hammett constants for estimating substituent NMR-shift effects on C4. Isomer determination can also be accomplished through interpretation of the fragmentation pattern observed in the mass spectrum. Keywords (Audience): Second-Year Undergraduate
Bioorganic & Medicinal Chemistry Letters, 2008
Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the c... more Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the compounds gave IC 50 values less than 1 lM, five exhibited values less than 0.40 lM, and two gave values less than 0.10 lM in a Leishmania donovani axenic amastigote assay. The activity of the diamidines strongly depends on the ring N-atom location relative to the amidine groups and correlates with DNA affinity. Transmission electron microscopy studies showed a dramatic dilation of the mitochondrion and evidence of disintegration of the kinetoplast of the amastigotes.
European Journal of Medicinal Chemistry, 2008
A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove o... more A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bis-guanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by DeltaT(m) values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.
Journal of Medicinal Chemistry, 2005
Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium... more Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed show IC 50 values of 5 nM or less against Trypanosoma brucei rhodesiense gave similar ones against Plasmodium falciparum (P.f.). , and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.
Bioorganic & Medicinal Chemistry, 2009
A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal... more A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC50 values less than 7 nM against T. b. r. Twelve of those exhibited IC50 values less than 6 nM against P. f. and six of those showed IC50 values ⩽0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.
![Research paper thumbnail of Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2- a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2- a]pyridines](https://attachments.academia-assets.com/50019829/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry, 2008
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
Journal of Medicinal Chemistry, 2006
Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium... more Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed show IC 50 values of 5 nM or less against Trypanosoma brucei rhodesiense gave similar ones against Plasmodium falciparum (P.f.). , and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.
Journal of The American Chemical Society, 2007
The classical model of DNA minor groove binding compounds is that they should have a crescent sha... more The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, binds specifically to a GC-rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in the development of DNA sequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs.
Archiv Der Pharmazie, 2008
In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumari... more In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (β-lactam) 3a–f, pyrrolidin-2-ones 4a–f, 2H-1,3,4-oxadiazoles 5a–f, and thiazolidin-4-ones 6a–f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a–f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.
Cheminform, 2009
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
a b s t r a c t 2-Cyanopyridine (1a), 4-cyanopyridine (1b), 2-cyanopyrazine (1c) on condensation ... more a b s t r a c t 2-Cyanopyridine (1a), 4-cyanopyridine (1b), 2-cyanopyrazine (1c) on condensation with mono amines (2aec) and diamines (4aec) in the presence of sodium methoxide as catalyst gave amidine derivatives (3aei) and bis amidine derivatives (5aei) in good yields. All these compounds were fully characterized by spectroscopic means and elemental analysis. On screening for anti-inflammatory activity and for in vitro anticancer activity compounds 5c and 5d exhibited good anti-inflammatory activity whereas compounds 5d breast (T47D), 5h, 5i lung (NCI H-522), 5i colon (HCT-15), 3c, 3h, 5i ovary (PA-1) and 3c, 5b, 5h liver (HepG2) exhibited good anticancer activity.
Medicinal Chemistry Research, 2011
The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5... more The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5-b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for carbonic anhydrase (CA) inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 11 and 12 exhibited better activities than the reference drug doxorubicin (IC50 = 71.8 μM) with IC50 values of 52.6 μM and 67.3 μM, respectively. On the other hand, compounds 6, 10, and 13 showed IC50 values (71.8 μM, 69.8 μM, and 70.8 μM, respectively) comparable to that of the reference drug doxorubicin. In addition, docking of the synthesized compounds into human carbonic anhydrase isozyme II (hCA II) active site was performed in order to predict the affinity and the orientation of these compounds at the isozyme active site. Also, the most active compounds, 11 and 12, were selected and evaluated for their ability to enhance the cell killing effect of γ-radiation.
European Journal of Medicinal Chemistry, 2010
Sulfonamide bearing compounds posses many types of biological activities and have recently been r... more Sulfonamide bearing compounds posses many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of twenty novel quinoline and pyrimido[4,5-b] quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for CA inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 6, 9 and 18 showed IC 50 values (72.9 mM, 72.1 mM and 71.9 mM, respectively) comparable to that of the reference drug doxorubicin (IC 50 ¼ 71.8 mM). On the other hand, compound 8 exhibited better activity than doxorubicin with an IC 50 value of 64.5 mM. Additionally, the most potent compounds 8 and 18 were evaluated for their ability to enhance the cell killing effect of g-radiation.
European Journal of Medicinal Chemistry, 2011
A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guani... more A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guanidines 7a,b and 8a,b as well as bis-imidamides 9–12a,b having a 1,3- or 1,4-diphenoxybenzene scaffold backbone were synthesized. The in vitro activity of the novel dications as antiprotozoal agents against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.) was assessed. Interestingly, six of the newly synthesized dications viz3a,b, 7a,b and 8a,b were more active against P.f. than the reference drug pentamidine. Also, some of the dications showed moderate antitrypanosomal activity. Thermal melting analysis of the novel dications was performed to determine their ligand-DNA relative binding affinities. Finally, docking of the dications with an AT rich DNA oligonucleotide was executed to understand their binding mode with the minor groove.Overlay of 7b (green) and pentamidine (red) showing their 2D binding interaction to the minor groove of the polydA.polydT DNA oligomer.► Novel dicationic flexible triaryl guanidines and imidamides were synthesized. ► All the dications were tested against T.b.r. and P.f. and compared to pentamidine. ► The guanidiniums and imidamides displayed good in vitro antiplasmodial activity. ► Tm data and docking showed these dications to bind as monocations to DNA.
Experimental Parasitology, 2011
Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affe... more Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT-rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD 50 values, good selectivity index, and good activity at 4°C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection.
Journal of The American Chemical Society, 2007
To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic ... more To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system while in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site show that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogs.
Journal of Chemical Education, 2006
ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-s... more ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-step synthesis and definitive characterization of a 3,5-diarylisoxazole via the chalcone and the chalcone dibromide is described. As each student prepares a differently substituted chalcone, and thus isoxazole, the project is individualized with regard to compound purification, characterization, and literature searches. To determine which isoxazole isomer was obtained from the synthesis, students compare their experimental 13C NMR data for C4 of the isoxazole to that predicted for each isomer. The predicted values are calculated using a formula that utilizes Hammett constants for estimating substituent NMR-shift effects on C4. Isomer determination can also be accomplished through interpretation of the fragmentation pattern observed in the mass spectrum. Keywords (Audience): Second-Year Undergraduate
Veterinary Parasitology, 2010
Biochemistry, 2005
The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades,... more The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades, this anti-trypanosomal agent has been known to intercalate into nucleic acids, with little preference for particular sequences. Only polydA-polydT tracts are relatively refractory to ethidium intercalation. In an effort to tune the sequence selectivity of known DNA binding agents, we report here the synthesis and detailed characterization of the mode of binding to DNA of a novel ethidium derivative possessing two guanidinium groups at positions 3 and 8. This compound, DB950, binds to DNA much more tightly than ethidium and exhibits distinct DNA-dependent absorption and fluorescence properties. The study of the mode of binding to DNA by means of circular and electric linear dichroism revealed that, unlike ethidium, DB950 forms minor groove complexes with AT sequences. Accurate quantification of binding affinities by surface plasmon resonance using A n T n hairpin oligomer indicated that the interaction of DB950 is over 10-50 times stronger than that of ethidium and comparable to that of the known minor groove binder furamidine. DB950 interacts weakly with GC sites by intercalation. DNase I footprinting experiments performed with different DNA fragments established that DB950 presents a pronounced selectivity for AT-rich sites, identical with that of furamidine. The replacement of the amino groups of ethidium with guanidinium groups has resulted in a marked gain of both affinity and sequence selectivity. DB950 provides protection against DNase I cleavage at AT-containing sites which frequently correspond to regions of enhanced cleavage in the presence of ethidium. Although DB950 maintains a planar phenanthridinium chromophore, the compound no longer intercalates at AT sites. The guanidinium groups of DB950, just like the amidinium group of furamidine (DB75), are the critical determinants for recognition of AT binding sites in DNA. The chemical modulation of the ethidium exocyclic amines is a profitable option to tune the nucleic acid recognition properties of phenylphenanthridinium dyes.
Journal of Chemical Education, 2006
ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-s... more ABSTRACT As a multistep synthetic project for the second-semester organic laboratory, the three-step synthesis and definitive characterization of a 3,5-diarylisoxazole via the chalcone and the chalcone dibromide is described. As each student prepares a differently substituted chalcone, and thus isoxazole, the project is individualized with regard to compound purification, characterization, and literature searches. To determine which isoxazole isomer was obtained from the synthesis, students compare their experimental 13C NMR data for C4 of the isoxazole to that predicted for each isomer. The predicted values are calculated using a formula that utilizes Hammett constants for estimating substituent NMR-shift effects on C4. Isomer determination can also be accomplished through interpretation of the fragmentation pattern observed in the mass spectrum. Keywords (Audience): Second-Year Undergraduate
Bioorganic & Medicinal Chemistry Letters, 2008
Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the c... more Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the compounds gave IC 50 values less than 1 lM, five exhibited values less than 0.40 lM, and two gave values less than 0.10 lM in a Leishmania donovani axenic amastigote assay. The activity of the diamidines strongly depends on the ring N-atom location relative to the amidine groups and correlates with DNA affinity. Transmission electron microscopy studies showed a dramatic dilation of the mitochondrion and evidence of disintegration of the kinetoplast of the amastigotes.
European Journal of Medicinal Chemistry, 2008
A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove o... more A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bis-guanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by DeltaT(m) values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.
Journal of Medicinal Chemistry, 2005
Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium... more Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed show IC 50 values of 5 nM or less against Trypanosoma brucei rhodesiense gave similar ones against Plasmodium falciparum (P.f.). , and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.
Bioorganic & Medicinal Chemistry, 2009
A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal... more A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC50 values less than 7 nM against T. b. r. Twelve of those exhibited IC50 values less than 6 nM against P. f. and six of those showed IC50 values ⩽0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.
Bioorganic & Medicinal Chemistry, 2008
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
Journal of Medicinal Chemistry, 2006
Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium... more Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed show IC 50 values of 5 nM or less against Trypanosoma brucei rhodesiense gave similar ones against Plasmodium falciparum (P.f.). , and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.
Journal of The American Chemical Society, 2007
The classical model of DNA minor groove binding compounds is that they should have a crescent sha... more The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, binds specifically to a GC-rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in the development of DNA sequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs.
Archiv Der Pharmazie, 2008
In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumari... more In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (β-lactam) 3a–f, pyrrolidin-2-ones 4a–f, 2H-1,3,4-oxadiazoles 5a–f, and thiazolidin-4-ones 6a–f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a–f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.
Cheminform, 2009
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
a b s t r a c t 2-Cyanopyridine (1a), 4-cyanopyridine (1b), 2-cyanopyrazine (1c) on condensation ... more a b s t r a c t 2-Cyanopyridine (1a), 4-cyanopyridine (1b), 2-cyanopyrazine (1c) on condensation with mono amines (2aec) and diamines (4aec) in the presence of sodium methoxide as catalyst gave amidine derivatives (3aei) and bis amidine derivatives (5aei) in good yields. All these compounds were fully characterized by spectroscopic means and elemental analysis. On screening for anti-inflammatory activity and for in vitro anticancer activity compounds 5c and 5d exhibited good anti-inflammatory activity whereas compounds 5d breast (T47D), 5h, 5i lung (NCI H-522), 5i colon (HCT-15), 3c, 3h, 5i ovary (PA-1) and 3c, 5b, 5h liver (HepG2) exhibited good anticancer activity.