Evaluation of some 1H-pyrazole derivatives as a dual acting antimalarial and anti-leishmanial agents.

The synthesis of a novel series of 1H-pyrazole derivatives was achieved by condensation of pyrazole aldehyde 1 with hydrazine hydrate to give hydrazone 7. On the other hand, cyclization of α,ß-unsaturated ketone counterpart 2 using hydrazine hydrate in liquid aliphatic acids rendered compounds 4-6 and hydrazine hydrate in ethanol afforded compound 3. The later was allowed to react with aroyl chloride giving rise to compounds 8, 9. All compounds were tested for their in vivo anti-malarial and in vitro antileishmanial activities. The anti-malarial activity was performed using Plasmodium berghei infected mice, while the anti-leishmanial activity of the compounds was determined against Leishmania aethiopica promastigotes using alamar blue reduction assay. Compound 3, 1-(4-methylphenyl)-3-phenyl-4-[3-(2-thienyl)-2-pyrazolin-5-yl]-1H-pyrazole, possessed the highest anti-malarial activity with suppression of 70.26%. The highest anti-leishmanial activity was exhibited by compound 2, 1-(4-methylphenyl)-3-phenyl-4-[1-(2-thienyl)-prop-2-en-1-one]-1H-pyrazole, with an IC50 of 0.079µg/ml. Hydrazone 7 showed appreciable dual anti-malarial (suppression = 62.30%) and anti-leishmanial activity (IC50 = 1.823µg/ml).

Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and 1H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC50 = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC50 = 3.130) and amphotericin B deoxycholate (IC50 = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.

Validation of an HPLC method for the simultaneous determination of diminazene diaceturate and phenazone in injectable veterinary granules and bulk powders.

A validated HPLC method for the simultaneous determination of diminazene diaceturate and phenazone has been established for the analysis of the compounds in veterinary granules for injection and in bulk powders. The compounds were separated using a Symmetry RP 18 analytical column and detected by UV absorbance at 250 nm. Linearity, accuracy as well as the intra-assay precision, inter-day precision and specificity of the method were established. The limits of detection and quantification were 3.2 and 9.7 µg mL-1 for diminazene diaceturate and 9.57 and 28.99 µg mL-1 for phenazone. Method had the potential to determine these drugs simultaneously from dosage forms without any interference with each other.

Synthesis, antimalarial, antileishmanial evaluation, and molecular docking study of some 3-aryl-2-styryl substituted-4(3H)-quinazolinone derivatives.

Quinazolinones are a diverse group of nitrogen-containing heterocyclic compounds with promising antimalarial and antileishmanial activities. Herein, some 3-aryl-2-styryl substituted-4(3H)-quinazolinones were synthesized via cyclization, condensation, and hydrolysis reactions. 1H NMR, FTIR and elemental microanalysis was used to verify the structures of the synthesized compounds. The in vivo antimalarial and in vitro antileishmanial activities of the target compounds were investigated using mice infected with Plasmodium berghi ANKA and Leishmania donovani strain, respectively. Among the test compounds, 8 and 10 showed better antimalarial activities with percent suppression of 70.01 and 74.18, respectively. In addition, (E)-2-(4-nitrostyryl)-3-phenylquinazolin-4(3H)-one (6) showed promising antileishmanial activity (IC50 = 0.0212 µg/mL). It is two and 150 times more active than the standard drugs amphotericin B deoxycholate (IC50 = 0.0460 µg/mL) and miltefosine (IC 50 = 3.1911 µg/mL), respectively. Its superior in vitro antileishmanial activity was supported by a molecular docking study conducted in the active site of Lm-PTR1. Overall, the synthesized 3-aryl-2-styryl substituted-4(3H)-quinazolinones showed promising antileishmanial and antimalarial activities and are desirable scaffolds for the synthesis of different antileishmanial and antimalarial agents.

Synthesis, modeling and biological evaluation of hybrids from pyrazolo[1,5c]pyrimidine as antileishmanial agents.

AIM: A new series of pyrazolo[1,5-c]pyrimidines were synthesized by different hybridization strategies. METHODOLOGY: All structures were confirmed by IR, 1H, 13C, 1H-13C heteronuclear multiple-quantum correlation (HMQC) spectra and microanalysis. They were evaluated for their in vitro antileishmanial activity against miltefosine and amphotericin B deoxycholate as reference drugs. RESULTS: The most active compounds 2a and 9a demonstrated superior potencies to miltefosine by ten- and six-fold, respectively, for the promastigote form, and by 5.5-fold for the amastigote form. Their binding scenario to Leishmania major pteridine reductase was rationalized by docking experiments. In addition, all compounds were safe for the experimental animals orally up to 150 mg/kg and parenterally up to 75 mg/kg. CONCLUSION: This study provides novel chemotype class for antileishmanial activity. [Formula: see text].

In vivo antimalarial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives.

BACKGROUND: Malaria is a neglected tropical parasitic disease affecting billons of people around the globe. Though the number of cases and deaths associated with malaria are decreasing in recent years, it is the most deadly disease in the world. This study aimed at investigating the in vivo antimalarial activities of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. RESULTS: The in vivo antimalarial activities of the test compounds (6-9 and 11-13) were investigated using the 4-day suppressive standard test in mice infected with chloroquine-sensitive Plasmodium berghei ANKA strain. The tested compounds showed significant antimalarial activities with mean percentage suppression of 43.71-72.86 % which is significantly higher than the negative control group (p < 0.05). Compounds 12 and 13 displayed better antimalarial activities from the group with mean percentage suppression of 67.60 and 72.86 % respectively. CONCLUSION: The tested compounds showed significant in vivo antimalarial activities in mice infected with P. berghi ANKA strain. Thus, 3-aryl-2-(substitutedstyryl)-4(3H)-quinazolinones represent a possible scaffold for the development of antimalarial agents.

Synthesis and antileishmanial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives.

BACKGROUND: Leishmaniasis is a neglected tropical parasitic diseases affecting millions of people around the globe. Quinazolines are a group of compounds with diverse pharmacological activities. Owing to their promising antileishmanial activities, some 3-aryl-2-(substitutedstyryl)-4(3H)-quinazolinones were synthesized in good yields (65.2% to 86.4%). RESULTS: The target compounds were synthesized by using cyclization, condensation, and hydrolysis reactions. The structures of the synthesized compounds were determined using elemental microanalysis, infrared (IR), and proton nuclear magnetic resonance ((1)H NMR). The in vitro antileishmanial activities of the synthesized compounds were evaluated using Leishmania donovani strain. All the synthesized compounds displayed appreciable antileishmanial activities (IC50 values, 0.0128 to 3.1085 µg/ml) as compared to the standard drug miltefosine (IC50 = 3.1911 µg/ml). (E)-2-(4-chlorostyryl)-3-p-tolyl-4(3H)-quinazolinone (7) is the compound with the most promising antileishmanial activities (IC50 = 0.0128 µg/ml) which is approximately 4 and 250 times more active than the standard drugs amphotericin B deoxycholate (IC50 = 0.0460 µg/ml) and miltefosine (IC50 = 3.1911 µg/ml), respectively. CONCLUSIONS: The results obtained from this investigation indicate that the synthesized and biologically evaluated quinazoline compounds showed promising antileishmanial activities and are good scaffolds for the synthesis of different antileishmanial agents.

Synthesis of some pyridazinylacetic acid derivatives as a novel class of monoamine oxidase-A inhibitors.

A series of new pyridazinylacetic acid derivatives were synthesized and have been investigated for their ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). All compounds were found to be more selective to the MAO-A isoform with compound 5d having the highest SI values. Computational study performed with a docking technique indicated the potential of these compounds in pyridazine-based MAO-A inhibitor drug development.