Reem K. Arafa

In vitro anticancer screening and radiosensitizing evaluation of some new quinolines and pyrimido[4,5-b]quinolines bearing a sulfonamide moiety

Sulfonamide bearing compounds possess 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 microM, 72.1 microM and 71.9 microM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 71.8 microM). On the other hand, compound 8 exhibited better activity than doxorubicin with an IC(50) value of 64.5 microM. Additionally, the most potent compounds 8 and 18 were evaluated for their ability to enhance the cell killing effect of gamma-radiation.

Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents.

Several derivatives with a quinoline scaffold and a flexible, semi-flexible or rigid side chains at position 8 of the quinoline ring were synthesized and assessed for their in vitro activity versus the human colon cancer cell line HT29 and the human breast cancer cell line MDA-MB231. The HT29 cell line was more refractory to the cytotoxic activity of some compounds, meanwhile all the quinoline derivatives except one displayed high to moderate activity against MDA-MB231 with IC50 values ranging between 4.6 and 48.2 μM. The most active derivative in this study against both tested cell lines was the Schiffs base 4e with IC50 of 4.7 and 4.6 μM against HT29 and MDA-MB231, respectively.

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

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.

Novel sulfonamides bearing pyrrole and pyrrolopyrimidine moieties as carbonic anhydrase inhibitors: Synthesis, cytotoxic activity and molecular modeling.

Novel pyrrole and pyrrolopyrimidine scaffold-based sulfonamides were designed and synthesized. The carbonic anhydrase (CA) inhibition ability of all derivatives was assessed against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated isoforms hCA IX and XII. Some of these sulfonamides were 6-8 fold more potent than the reference drug acetazolamide (AZA, Ki = 5.7 nM)) against hCA XII showing subnanomolar activity. The in vitro cytotoxicity of these derivatives was evaluated against MCF-7, where some derivatives were more cytotoxic than doxorubicin (IC50 = 8.02 μM) displaying IC50 values between 6.46 and 7.56 μM. Docking of these sulfonamides with CA XII was performed and their binding modes were comparable with that of AZA.

Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures

Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.

Novel anti-HIV-1 NNRTIs based on a pyrazolo[4,3-d]isoxazole backbone scaffold: design, synthesis and insights into the molecular basis of action

A series of novel pyrazolo[4,3-d]isoxazoles was synthesized employing the thioamide synthon 3 to obtain the phenyldiazenylthiazolyl derivatives 7a–f, the thiazolyl derivative 9, the carbohydrazonamide 12 and the triazinyl counterparts 14a–c. The prepared compounds were screened for their antiviral activities against two viral strains of HIV-1 (RF and IIIB). All the compounds exhibited a highly potent antiviral capacity, having submicromolar to subnanomolar EC50 values with all derivatives being more active against the tested HIV strains than the reference drug efavirenz. The therapeutic index of these novel pyrazoloisoxazoles was also evaluated against the host cells CEM-SS or MT-4 and they exhibited a high therapeutic window. To further investigate the molecular basis of their actions, the inhibitory ability of these compounds was bioscreened against the HIV-1 viral enzyme reverse transcriptase (RT). The observed very potent inhibitory power of the pyrazolo[4,3-d]isoxazoles against RT prompted a molecular docking study to try exploring the potential binding modes of these compounds with their respective molecular targets. Finally, in vitro exploration of the metabolic stability of this series of compounds was evaluated by employing a rat-plasma half-life assay and they demonstrated reasonable hydrolytic resistance.

Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3-dipyridylbenzene derivatives

4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤ 10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.

Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense and Plasmodium falciparum

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 IC(50) values less than 7 nM against T. b. r. Twelve of those exhibited IC(50) values less than 6 nM against P. f. and six of those showed IC(50) 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.

Molecular modeling, spectral, and biological studies of 4-formylpyridine-4N-(2-pyridyl) thiosemicarbazone (HFPTS) and its Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Cd(II), Hg(II), and UO2(II) complexes

The present work describes the preparation and characterization of some metal ion complexes derived from 4-formylpyridine-4N-(2-pyridyl)thiosemicarbazone (HFPTS). The complexes have the formula; [Cd(HFPTS)2H2O]Cl2, [CoCl2(HPTS)]·H2O, [Cu2Cl4(HPTS)]·H2O, [Fe (HPTS)2Cl2]Cl·3H2O, [Hg(HPTS)Cl2]·4H2O, [Mn(HPTS)Cl2]·5H2O, [Ni(HPTS)Cl2]·2H2O, [UO2(FPTS)2(H2O)]·3H2O. The complexes were characterized by elemental analysis, spectral (IR, 1H-NMR and UV–Vis), thermal and magnetic moment measurements. The neutral bidentate coordination mode is major for the most investigated complexes. A mononegative bidentate for UO2(II), and neutral tridentate for Cu(II). The tetrahedral arrangement is proposed for most investigated complexes. The biological investigation displays the toxic activity of Hg(II) and UO2(II) complexes, whereas the ligand displays the lowest inhibition activity toward the most investigated microorganisms.

In vitro activity and preliminary toxicity of various diamidine compounds against Trypanosoma evansi.

Trypanosoma evansi is an animal pathogenic protozoan, causing a wasting disease called Surra, which is broadly distributed in a wide range of mammalian hosts. Chemotherapy is the most efficient control method, which depends on four drugs. Unfortunately, with the appearance of resistance to these drugs, their effective use is threatened, emphasising a need to find new drugs. Diamidines bind to the minor groove of DNA at AT-rich sites and exert their anti-trypanosomal activity by inhibiting one or more DNA dependent enzymes or by directly impeding the transcription process. In total, 67 novel diamidine compounds were tested in vitro to determine activity against an animal pathogenic Chinese kinetoplastic T. evansi strain. In comparison, a human pathogenic Trypanosoma brucei rhodesiense strain and a P2 transporter knock out of a Trypanosoma brucei brucei strain were also tested. All diamidine compounds tested in this study against T. evansi produced inhibitory concentration (IC(50)) values below 50 nM. The results demonstrate that these compounds are highly active against T. evansi in vitro. In addition, preliminary in vivo toxicity tests were performed on all 67 diamidines with 69% of the compounds showing no acute toxicity at an intra-peritoneal dose of 100mg/kg.