Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.

Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.

Evaluation of analogs of reutericyclin as prospective candidates for treatment of staphylococcal skin infections.

The potential for reutericyclin derivatives to be used as topical antibiotics to treat staphylococcal skin infections was investigated. All reutericyclins inhibited the growth of clinical isolates of drug-resistant Staphylococcus aureus. Unlike the standard topical agent mupirocin, most reutericyclin derivatives eradicated staphylococcal biofilms. Moreover, two compounds formulated in hydrophilic petrolatum (10%, wt/wt) were efficacious in treating S. aureus superficial skin infections in mice. These data exemplify the prospect of developing reutericyclins as new topical antibiotics.

Protective effect of tenuazonic acid against dimethyl benz(a)antracene-induced skin carcinogenesis in mice.

Anticarcinogenic potential of tenuazonic acid (TA), a mycotoxin isolated from a fungus, Alternaria alternata, on skin tumorigenesis induced by 7,12-dimethyl benz(a) antracene (DMBA) was investigated. Female Swiss albino mice were exposed topically to 100 nmole of DMBA twice weekly for 20 weeks. Another group of animals was treated with 250 microg TA in acetone daily for a period of 1 week, followed by the same dose of TA prior to every application of DMBA. At the end of 14 weeks, all the animals in the group that was exposed to DMBA alone developed tumors, while 40% of the animals in TA-treated group were found to be tumor free. After 20 weeks, there was no further increase in the number of tumor-bearing animals. Results indicated that prior application of TA significantly delayed the onset of tumorigenesis and also reduced the cumulative number of tumors per tumor-bearing animals. The present studies reveal the antitumor and protective potential of TA against polycyclic aromatic hydrocarbon induced skin carcinogenesis.

Inhibition of mouse skin tumor promotion by tenuazonic acid.

Tenuazonic acid (TA) was topically applied to the interscapular region of Swiss albino mice at different doses before the application of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Skin from the painted area was examined for ornithine decarboxylase (ODC) enzyme estimation. It was observed that TA inhibited TPA induced ODC activity. The inhibitory effect of TA was also found in mouse skin tumor promotion in the two stage initiation promotion protocol. There was a remarkable delay in the latency period and decrease in the number of tumors developed and the percentage of tumor bearing animals after TA treatment.