ABSTRACT
Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.
Subject(s)
Central Nervous System Agents/pharmacology , Semicarbazides/pharmacology , Thiadiazoles/pharmacology , Triazoles/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Analgesics/toxicity , Animals , Anxiety/drug therapy , Body Temperature/drug effects , Central Nervous System Agents/chemical synthesis , Central Nervous System Agents/chemistry , Central Nervous System Agents/toxicity , Depression/drug therapy , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Mice , Molecular Structure , Motor Activity/drug effects , Nociceptive Pain/drug therapy , Seizures/drug therapy , Semicarbazides/chemistry , Semicarbazides/toxicity , Sleep/drug effects , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/toxicity , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/toxicityABSTRACT
Twelve 4-benzoyl-1-dichlorobenzoylthiosemicarbazides have been tested as potential antibacterials. All the compounds had MICs between 0.49 and 15.63 µg/ml toward Micrococcus luteus, Bacillus cereus, Bacillus subtilis and Staphylococcus epidermidis indicating, in most cases, equipotent or even more effective action than cefuroxime. In order to clarify if the observed antibacterial effects are universal, further research were undertaken to test inhibitory potency of two most potent compounds 3 and 11 on clinical isolates of Staphylococcus aureus. Compound 11 inhibited the growth of methicillin-sensitive S. aureus (MSSA) at MICs of 1.95-7.81 µg/ml, methicillin-resistant S. aureus (MRSA) at MICs of 0.49-1.95 µg/ml and MDR-MRSA at MIC of 0.98 and 3.90 µg/ml, respectively. Finally, inhibitory efficacy of 3 and 11 on planktonic cells and biofilms formation in clinical isolates of S. aureus and Haemophilus parainfluenzae was tested. The majority of cells in biofilm populations of MSSA and MRSA were eradicated at low level of 3, with MBICs in the range of 7.82-15.63 µg/ml.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Drug Design , Gram-Negative Bacteria/drug effects , Semicarbazides/pharmacology , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Semicarbazides/chemical synthesis , Semicarbazides/chemistry , Structure-Activity RelationshipABSTRACT
In the present article, we describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile and molecular modelling evaluation. We found that one of the tested compounds, compound 7, significantly inhibits activity of Staphylococcus aureus DNA gyrase with an IC(50) below 15 µM. Besides, this compound displays antibacterial activity on reference Staphylococuss spp. and Enterococcus faecalis strains as well as clinical S. aureus isolates at non-cytotoxic concentrations in mammalian cells with MIC values ranging from 16 to 32 µg/mL thereby indicating, in some cases, equipotent or even more effective action than standard drugs such as vancomycin, ampicillin and nitrofurantoin. The computational studies showed that both molecular geometry and the electron density distribution have a great impact on antibacterial activity of thiosemicarbazide derivatives.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Gyrase/metabolism , Enterococcus faecalis/enzymology , Models, Molecular , Semicarbazides/pharmacology , Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Line , Cell Survival/drug effects , DNA Topoisomerases, Type II , Dose-Response Relationship, Drug , Enterococcus faecalis/drug effects , Fibroblasts/drug effects , HeLa Cells , Humans , Mice , Microbial Sensitivity Tests , Molecular Structure , Semicarbazides/chemical synthesis , Semicarbazides/chemistry , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistryABSTRACT
A series of six 2,5-disubstituted 1,3,4-thiadiazole derivatives was synthesized and examined for cytotoxic activity in MCF-7 and MDA-MB-231 breast cancer cells. MTT assay confirmed that 2-(3-fluorophenylamino)-5-(3-hydroxyphenyl)-1,3,4-thiadiazole (2), 2-(4-bromophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (3), 2-(4-fluorophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (4), had ability to inhibit MCF-7 and MDA-MB-231 cells proliferation. The IC50 values for the mentioned compounds ranged between 120 and 160 µM (with respect to MCF-7 cells) and from 70 to 170 µM (with respect to MDA-MB-231 cells). It turned out, moreover, that compound 2 is a human topoisomerase II (topoII) catalytic inhibitor whereas the two other compounds (i.e. 3 and 4) are capable of stabilizing DNA-topoII cleavage complex and thus are topoII poisons.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Topoisomerases, Type II/metabolism , Thiadiazoles/pharmacology , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Tumor Cells, CulturedABSTRACT
This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potent analgesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4-(4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results.
