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Differently substituted isonicotinoylhydrazothiazoles and isonicotinoyl-N4-substituted thiosemi-carbazides have been prepared and characterized by means of elemental analysis, 1H-NMR, 13C-NMR, and Mass spectrometry. All the synthesised compounds have been screened in order to evaluate their antimycobacterial activity in vitro. Some of the new compounds showed activity towards M. tuberculosis H37R and M. Marinum in the millimolar range.

The antimycobacterial activities of two new S-alkylisothiosemicarbazone derivatives (1i and 1f) against 32 Mycobacterium avium isolates were investigated. The minimum inhibitory concentrations (MICs) were significantly lower than those of rifampicin and other reference drugs. The two derivatives also showed excellent intracellular activity against M. avium residing in the macrophage-like J774 cells. Interestingly, the combination of subinhibitory concentrations of 1i and rifabutin or rifampicin induced a potent synergistic effect, as determined by the fractional inhibitory concentration indexes (FICIs) ranging between 0.103 and 0.412. Such synergistic effect resulted in a 81-fold and 139-fold reduction of the MICs of rifabutin and rifampicin, respectively. Enhancement of intracellular activity of rifabutin by the S-alkylisothiosemicarbazone derivative 1i was also observed. Results indicate that S-alkylisothiosemicarbazones can be useful in the therapy and prophylaxis of M. avium infections and can represent a template for the development of novel antimycobacterial drugs. Furthermore, as a consequence of their ability to enhance the activity of rifamycins, a reduction of drug interactions following the co-administration of protease inhibitors could be achieved by lower doses of rifampicin and rifabutin.

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4 microg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity.

Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were added to the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. The most active derivatives showed activity between 0.125-0.5 microg/mL (better than 16 and streptomycin) and protection index (64-256) higher than 16 (4) and similar to isoniazid and streptomycin (128).

In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand-based virtual library was applied. This used both an in silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25 microg mL(-1). Based on these compounds, two series of derivatives were synthesized by both parallel solution-phase and microwave-assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.

Objectives: The aim of this study was to investigate the in vitro antifungal activity of an isothiosemicarbazone cyclic analogue against isolates of Candida spp. including fluconazole-resistant Candida albicans. Methods: We investigated the activity of 2-cyclohexylidenhydrazo-4-phenyl-thiazole (EM-01D2) against 114 clinical isolates of Candida spp., representing five different species, by microdilution, according to the NCCLS method 27-A. The activity against C. albicans biofilms was also investigated. Toxicity in vitro was evaluated by MTT reduction assay. Results: EM-01D2 demonstrated low toxicity, broad spectrum, fungicidal activity and was active against C. albicans and Candida krusei at concentrations lower than those shown by amphotericin B and fluconazole (P < 0.05). It maintained potent in vitro activity against fluconazole-resistant C. albicans isolates. Fungicidal activity occurred at concentrations 1‐2 doubling dilutions greater than the corresponding MICs, and time‐kill analysis indicated that a 99.9% loss of C. albicans viability occurred after 6 h of incubation in the presence of EM-01D2 at concentrations equal to four times the MIC. EM-01D2 was also active in inhibiting the growth of C. albicans ATCC 10231 biofilms, even though such inhibition occurred at concentrations higher than the MICs determined under planktonic growth conditions. However, when C. albicans biofilms were pre-exposed to subinhibitory concentrations of EM-01D2, a reduction of MIC50 of amphotericin B was observed. Conclusions: Based on these results, EM-01D2 could represent a template for the development of novel fungicidal agents.