Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.

By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.

The synthesis of a new series of 5-or 6-methyl-2-(2,4-disubstituted phenyl) benzoxazoles (4, 5) is described in order to determine their antimicrobial activities and feasible structure-activity relationships. The synthesized compounds were tested in vitro against three Gram-positive bacteria, three Gram-negative bacteria and the yeast Candida albicans, in comparison with several control drugs. Microbiological results exhibited that the synthesized compounds possess a broad spectrum of antibacterial activity against the tested microorganisms. The compounds 4b and 4c indicated some antibacterial activity against Staphylococcus aureus having a minimum inhibitory concentration (MIC) of 12.5 micrograms/ml. Moreover, the compound 5a revealed a significant antibacterial activity against the enterobacter Pseudomonas aeruginosa showing a MIC value of 25 micrograms/ml, i.e. more potent than the control drugs tetracycline and streptomycin. For the antimycotic activity against the yeast C. albicans, the derivative 4c was found to be more active than the other synthesized compounds with a MIC value of 12.5 micrograms/ml, but one-fold less potent than the control drugs oxiconazole and haloprogin.

The synthesis and microbiological activity of a new series of 5(or 6)-methyl-2-substituted benzoxazoles (IVa-n) and benzimidazoles (Va-h) were described. The in vitro microbiological activity of the compounds was determined against gram-positive, gram-negative bacteria and the yeast Candida albicans in comparison to reference drugs. Microbiological results indicated that the derivatives possessed a broad spectrum of activity against the tested microorganisms and the compounds IVa-g, IVi-k, IVn, Vb-c and Vh showed significant activity against Pseudomonas aeruginosa having MIC values of 25 micrograms/ml, providing higher potencies than the reference drugs tetracycline and streptomycin. Moreover, the derivative 5-methyl-2-(p-chlorobenzyl)benzoazole (IVb) possessed the same potency against Candida albicans as the reference drugs oxiconazole and haloprogin having a MIC value of 6.25 mg/ml. However, none of the derivatives showed a better spectrum of activity than the reference drugs.

Superficial fungal infections are common. Most diagnoses of fungal infections of the skin can be made by physical examination, assisted by the use of a Wood's lamp, skin scrapings for microscopic examination, and fungal cultures. Dermatophyte infections are common at all ages, in both sexes, and they have a worldwide distribution. These infections include tinea capitis, tinea cruris, tinea pedis, tinea corporis, tinea manuum and tinea barbae. Tinea versicolor, caused by Malassezia furfur, and candidal infections are also common. Treatment modalities include oral and topical agents. Good personal hygiene is an important adjunct to antifungal therapy. Decisions regarding the appropriateness of therapy in a given patient must take into account the extent and location of the infection, the benefits and risks of each of the treatments, and cost. Oral therapies include griseofulvin, ketoconazole, and itraconazole. There are a large variety of topical treatments, including nystatin, selenium sulfide, tolnaftate, haloprogin, miconazole, clotrimazole, and sodium thiosulfate. Important to successful treatment is compliance with what is sometimes a long course of treatment, and good personal hygiene.

2-(2,3,3-Triiodoallyl)tetrazole (ME1401), a novel antifungal agent, showed therapeutic effectiveness in topical treatment of experimental dermal infections with Trichophyton mentagrophytes and Candida albicans in guinea-pigs. Addition of diethyl sebacate to the ME1401 preparations increased its in vivo antifungal activity and its penetration into the skin. When the estimation of efficacy of treatment with active formulations was made on the basis of skin lesion and the rate of negative skin cultures in comparison with those for infected, untreated or placebo-treated controls, the in vivo activity of 0.5% ethanol tincture or gel of ME1401 was comparable to that of reference antimycotic drugs such as clotrimazole, haloprogin and others. Pharmacokinetic studies in the experimental animals demonstrated that ME1401 was unstable in vivo, being readily converted to an active metabolite 2-(3-iodopropargyl)tetrazole (CN144) first and then to 2-propargyltetrazole (CN151). CN144 showed potent in vitro and in vivo antifungal activities, while the in vitro activity of CN151 was negligible.

A shortened modification of Dittmar's in vitro human skin assay reliably predicts the efficacy of topical antifungals against ringworm fungi. Cadaver skin was treated with the test agents for 4 or 24 h. After heat separation of the epidermis for one minute at 60 degrees C, the undersurface was point inoculated with a spore suspension of T. mentagrophytes. In untreated skin fluffy, 3 mm colonies develop after 4 to 5 days of incubation. Effective fungistats produce complete inhibition of growth. Commercial formulations of the imidazoles, tolnaftate and ciclopirox were highly effective. Haloprogin, undecylenate, and hydroxyquinoline in proprietary form were inactive. There was a high correspondence between in vitro and in vivo effectiveness. The method should be useful for screening new antifungals and for optimal selection of vehicles.

The in vitro antifungal activity of ME1401, a potential topical antifungal agent, was compared with that of haloprogin, clotrimazole, miconazole, tolnaftate, and ciclopirox olamine by using an agar dilution procedure. ME1401 showed a broad antifungal spectrum and inhibited all of the 428 strains of 52 species of pathogenic yeasts and filamentous fungi tested at concentrations ranging from 0.01 to 12.5 micrograms/ml. In general, the activity of ME1401 was comparable or superior to that of clotrimazole and was greater than that of haloprogin and the other reference drugs under the conditions used. Only tolnaftate was superior to ME1401 in its activity against clinical isolates of Trichophyton rubrum. ME1401 showed no cross-resistance with any of the reference drugs and exhibited potent fungicidal activity.

There is a wide variety of highly effective topical antifungal agents available for the treatment of dermatophytosis. In more widespread infections or those involving hair or nails oral therapy with griseofulvin or ketoconazole can be used. With both forms of therapy certain types of dermatophyte infection are clinically resistant to treatment. These include onychomycosis, infections of the sole caused by T.rubrum and certain forms of tinea capitis (e.g. favus) or tinea corporis. In future consideration needs to be given to find the optimum duration and frequency of treatment and better methods of allowing penetration of drugs into nails and heavely keratinised sites.

The type of fungal infection and the immunologic status of the patient determine whether drug therapy should be used. Amphotericin B is the single most important antifungal agent for the treatment of systemic mycoses. Flucytosine is given adjunctively with amphotericin B. Miconazole, a new parenteral agent, may be useful in treating candidiasis, cryptococcosis, paracoccidioidomycosis and coccidioidomycosis. Potassium iodide is used to treat lymphocutaneous sporotrichosis, bronchopulmonary geotrichosis and chromoblastomycosis. Nystatin, tolnaftate, clotrimazole and haloprogin are used for mucocutaneous infections. Griseofulvin is limited to the treatment of skin and nail infections caused by dermatophytes.