ABSTRACT
New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their structures were identified by different spectroscopic data (1 H NMR, 13 C NMR, two-dimensional NMR, mass spectrometry, elemental analysis, and single-crystal X-ray analysis). The mechanism describing the formation of the products was also discussed. The antidiabetic activity of the isolated products was investigated histochemically. The synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in streptozotocin-induced diabetic mice. Compounds 5a and 5c significantly lowered the blood glucose level to 103.3 ± 1.8 and 102 ± 3.9 mg/dl, respectively. Also, they caused a significant decrease in malondialdehyde levels and normalized the glutathione levels in streptozotocin-induced diabetic mice, compared with the diabetic group. The results suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the development of oxidative stress in diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Drug Design , Hydrazines/pharmacology , Hypoglycemic Agents/pharmacology , Thioamides/pharmacology , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Dose-Response Relationship, Drug , Hydrazines/chemical synthesis , Hydrazines/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Mice , Molecular Structure , Oxidative Stress/drug effects , Streptozocin , Structure-Activity Relationship , Thioamides/chemical synthesis , Thioamides/chemistryABSTRACT
Mercapto-substituted 1,2,4-triazoles are very interesting compounds as they play an important role in chemopreventive and chemotherapeutic effects on cancer. In recent decades, literature has been enriched with sulfur- and nitrogen-containing heterocycles which are used as a basic nucleus of different heterocyclic compounds with various biological applications in medicine and also occupy a huge part of natural products. Therefore, we shed, herein, more light on the synthesis of this interesting class and its application as a biologically active moiety. They might also be suitable as antiviral and anti-infective drugs.
Subject(s)
Anti-Infective Agents/pharmacology , Antiviral Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Triazoles/chemistry , Triazoles/pharmacology , Viruses/drug effects , Anti-Infective Agents/chemistry , Antiviral Agents/chemistry , HumansABSTRACT
The reactions of dialkyl acetylenedicarboxylates with various 2-oxo-acenaphthoquinylidene- and 4-acetyl[2.2]paracyclophanylidene-thiosemicarbazones were investigated. Using simple experimental procedures, 1,3-Thiazolidin-4-ones derived from acenaphthequinone or [2.2]paracyclophane were obtained as major products in good yields. In the case of allyl derivative of acenaphthoquinylidene-thiosemicarbazones, a complex structure of tetramethyl 5-(2-(((Z,E)-N-allyl-N'-(2-oxoacenaphthylen-1(2H)-ylidene)carbamohydrazonoyl)thio)-1,2,3-tris-(methoxycarbonyl)-cyclopropyl)-4-methoxy-7-oxabicyclo[2.2.1]hepta-2,5-diene-1,2,3,6-tetracarboxylate was formed. Single crystal X-ray analysis was used as an efficient tool to confirm the structure of the synthesized compounds as well as different spectroscopic data (1H-NMR, 13C-NMR, 2D-NMR, mass spectrometry and elemental analysis). The mechanism of the obtained products was discussed.
Subject(s)
Acenaphthenes/chemistry , Thiazolidinediones/chemistry , Thiosemicarbazones/chemistry , Chemistry Techniques, Synthetic , Molecular Structure , Spectrum AnalysisABSTRACT
A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-2-ylidene)propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated Annexin V expression, enhanced caspase 3/7 activation and PARP cleavage. In this study, we present the potential for designing novel propellanes to provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.
