Synthesis, antimicrobial evaluation and docking studies of new pyrazolone derivatives

Purpose: To synthesize new antimicrobial azo-pyrazolone derivatives III & IV and evaluate their antimicrobial activities using a combination of in vitro and molecular docking studies.Methods: Azopyrazolone compounds were prepared from the reaction of substituted aniline diazonium with ethyl acetoacetate to give azoxobutyric acid derivatives (II) which were then reacted with phenyl hydrazine or hydrazine hydrate. The pyrazolone derivatives (IV) were acetylated with glacial acetic acid to yield new acetylated pyrazolones (V). An agar dilution method was used to demonstrate the  antimicrobial activities of the pyrazolone derivatives and their minimum inhibitory concentration (MIC) values calculated. Molecular docking studies were employed to further evaluate the most active compounds (on the basis of the MICs obtained).Results: The new pyrazolone derivatives showed varying antimicrobial activities (from negligible to strong) against a number of microorganisms. Derivatives IIIb and Vb showed potent activities against Bacillus subtilis, Sarcina lutea, Staphylococcus aureus and Enterococcus faecalis. However, the new compounds did not show antifungal activity. Molecular docking results for compounds IIIb and Vb wereconsistent with their antimicrobial activities and proved that the compounds inhibited glucosamine-6-phosphate synthase.Conclusion: The new dichloropyrazolone compounds IIIa and Vb possess potent antimicrobial activities. These compounds have promising potential for use as new antibacterial agents or as templates for the design of new antimicrobial drugs.Keywords: Azo-pyrazolone, Dichloropyrazolone, Antimicrobial, Molecular dockin

Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei

Lipophilic bisphosphonium salts are among the most promising antiprotozoal leads currently under investigation. As part of their preclinical evaluation we here report on their mode of action against African trypanosomes, the etiological agents of sleeping sickness. The bisphosphonium compounds CD38 and AHI-9 exhibited rapid inhibition of T. brucei growth, apparently the result of cell cycle arrest that blocked the replication of mitochondrial DNA, contained in the kinetoplast, thereby preventing the initiation of S-phase. Incubation with either compound led to a rapid reduction in mitochondrial membrane potential, and ATP levels decreased by approximately 50% within 1 h. Between 4 and 8 h, cellular calcium levels increased, consistent with release from the depolarized mitochondria. Within the mitochondria, the Succinate Dehydrogenase complex (SDH) was investigated as a target for bisphosphonium salts, but while its subunit 1 (SDH1) was present at low levels in the bloodstream form trypanosomes, the assembled complex was hardly detectable. RNAi knockdown of the SDH1 subunit produced no growth phenotype, either in bloodstream or in the procyclic (insect) forms and we conclude that in trypanosomes SDH is not the target for bisphosphonium salts. Instead, the compounds inhibited ATP production in intact mitochondria, as well as the purified F1 ATPase, to a level that was similar to 1 mM azide. Co-incubation with azide and bisphosphonium compounds did not inhibit ATPase activity more than either product alone. The results show that, in Trypanosoma brucei, bisphosphonium compounds do not principally act on succinate dehydrogenase but on the mitochondrial FoF1 ATPase

Synthesis, antimicrobial activities and GAPDH docking of novel 1, 2, 3-triazole derivatives

Purpose: To synthesize new triazole derivatives in order to overcome the problem of side effects of antimicrobial agents and microbial resistance, while broadening the spectrum of antimicrobial activity. Methods: The starting triazole, compound 1, was prepared through click chemistry and reacted with chloroacetyl chloride to yield compound II. Triazole 1 was reacted with acids and aldehydes to produce oxadiazole (III) and azomethine (IV) which cyclized in acetic anhydride to give a new acetylated oxadiazole (V). Minimum inhibitory concentration (MIC) and resorufin assays were used for antibacterial and anti-parasitic screening, respectively. Compounds II and IVb were subjected to molecular docking studies using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Molecular Operating Environment (MOE) program. Results: Novel oxazole-triazole derivative (III) showed high activity against Pseudomonas aeruginosa and moderate activity against Staphylococcus epidermidis, whereas compound IVc showed moderate activity against Staphylococcus epidermidis. Chloro-acetyl-triazole II and 2-hydroxyphenyl-triazole Schiff base (Ivb) showed pronounced activity against the kinetoplastid parasites, Leishmania major, Leishmania mexicana and Trypanosoma brucei. Conclusion: The new synthesized triazoles represent a new antimicrobial scaffold and identifies potential new lead compounds for follow-up and for further mechanistic studies

Synthetic ligustrazine based cyclohexanone and oxime analogs as Anti-Trypanosoma and Anti-Leishmanial agentes

In the present study a series of 34 synthetic ligustrazine-containing α, β-Unsaturated carbonyl-based compounds and oximes, recognized as anticancer compounds were assessed against protozoa of the Trypanosoma and Leishmania species. Ligustrazine, chemically known as tetramethylpyrazine (TMP), was selected as the core moiety for the synthesis of α, β-Unsaturated carbonyl-based compounds and these compounds were selected as precursors for the synthesis of new oximes. Some derivates, including 5f and 6i, showed multiple activities against all tested strains. In particular compounds 5f and 8o are the most potent and they are, therefore, potential candidates for trypanosomiasis and leishmaniasi

Synthesis, antimicrobial activities and GAPDH docking of new 1,2,3-triazole derivatives

Purpose: To synthesize new triazole derivatives in order to overcome the problem of side effects of antimicrobial agents and microbial resistance, while broadening the spectrum of antimicrobial activity. Methods: The starting triazole, compound 1, was prepared through click chemistry and reacted with chloroacetyl chloride to yield compound II. Triazole 1 was reacted with acids and aldehydes to produce oxadiazole (III) and azomethine (IV) which cyclized in acetic anhydride to give a new acetylated oxadiazole (V). Minimum inhibitory concentration (MIC) and resorufin assays were used for antibacterial and anti-parasitic screening, respectively. Compounds II and IVb were subjected to molecular docking studies using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Molecular Operating Environment (MOE) program. Results: Novel oxazole-triazole derivative (III) showed high activity against Pseudomonas aeruginosa and moderate activity against Staphylococcus epidermidis, whereas compound IVc showed moderate activity against Staphylococcus epidermidis. Chloro-acetyl-triazole II and 2-hydroxyphenyl-triazole Schiff base (Ivb) showed pronounced activity against the kinetoplastid parasites, Leishmania major, Leishmania mexicana and Trypanosoma brucei. Conclusion: The new synthesized triazoles represent a new antimicrobial scaffold and identifies potential new lead compounds for follow-up and for further mechanistic studies

Docking studies and antiprotozoal activity of secondary metabolites isolated from Scrophularia syriaca Benth. growing in Saudi Arabia

Phytochemical study of the ethanolic extract of Scrophularia syriaca Benth. was attained by chromatographic and spectroscopic procedures, which resulted in isolation of eight compounds; 6-O-α-L- rhamnopyranosylcatalpol (1), scropolioside B (2), gmelinoside-L (3), 8-acetyl harpagide (4), scropolioside D (5), scropolioside D2 (6), quercetin (7) and kaempferol-3-O-rutinoside (8). The antiprotozoal activity was evaluated against Trypanosoma brucei brucei (s427-WT), Trypanosoma brucei brucei (TbAT1-B48), Leishmania major and Leishmania mexicana. Compounds 2, 5, 7 and 8 exhibited mild to moderate activities against kinetoplastid parasites compared to pentamidine positive control, the mechanism of antiprotozoal activity was predicted by the molecular docking studies on the target enzyme Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH)