In vitro susceptibility of Sporothrix spp. to complexes coordinated with Co(II) and cobalt chloride hexahydrate

Abstract Sporothrix spp. are the major dimorphic fungus associated with a type of subcutaneous mycosis, sporotrichosis. The limitation of antifungal availability and the past reports of in vitro resistance of Sporothrix spp. clinical isolates makes it important to search for new compounds with antifungal activities. In this study, we therefore evaluate the in vitro activities of complexes coordinated with Co(II) and cobalt chloride hexahydrate against clinical isolates of Sporothrix spp. Broth microdilution test was performed as per M38-A2 from CLSI (2008) in duplicate for 31 clinical isolates of Sporothrix spp. (27 S. brasiliensis e 04 S. schenckii stricto sensu). The antifungal activities of the complexes coordinated with Co(II) and cobalt chloride hexahydrate were detected at a concentration range of 32-128 µg/mL for all isolates. None of the compounds demonstrated any cytotoxicity (to macrophage cells) at the concentration of 200 µg/mL. The activity against Sporothrix spp. recorded in this study instigate the continuity of experimental studies with Co(II) to search for the mechanisms of antifungal action as well as to evaluate its interaction with the commercial antifungal drugs.

Benzo[a]phenazine derivatives: Promising scaffolds to combat resistant Mycobacterium tuberculosis.

The continuous emergence of resistant Mycobacterium tuberculosis keeps tuberculosis (TB) treatment options still insufficient, and new therapeutic alternatives are urgently needed. Considering the antimycobacterial activity of phenazine derivatives previously reported by our research group, we aimed to explore possible applications to circumvent the resistance in M. tuberculosis. Firstly, we evaluated the antimicrobial activity of seven benzo[a]phenazine derivatives against eleven M. tuberculosis strains: ten resistant and one susceptible (H37 Rv). Then, we determined the cytotoxicity of benzo[a]phenazine derivatives and investigated the possible mechanism of action of the most promising compound. Among them, compound 10 was the only one active against all strains evaluated, with a minimum inhibitory concentration between 18.3 and 146.5 µM. For some resistant strains, this compound showed antimicrobial activity higher than rifampicin and it was also active against MDR strains, indicating an absence of cross-resistance with anti-TB drugs. Also, 10 showed a pharmacological safety for further in vivo studies and its mechanism of action seems to be related to oxidative stress. Thus, our findings indicate that benzo[a]phenazine derivatives are promising scaffolds for the development of new anti-TB drugs, mainly focusing on the treatment of resistant TB cases.

Crystal structure of ethyl (E)-4-(4-chlorophen-yl)-4-meth-oxy-2-oxobut-3-enoate.

In the title compound, C13H13ClO4, the dihedral angle between the chloro-benezene ring and the least-squares plane through the 4-meth-oxy-2-oxobut-3-enoate ethyl ester residue (r.m.s. deviation = 0.0975 Å) is 54.10 (5)°. In the crystal, mol-ecules are connected by meth-oxy-ketone and benzene-carboxyl-ate carbonyl C-H⋯O inter-actions, generating a supra-molecular layer in the ac plane.

2-[5-(2-Methyl-phen-yl)-3-(2-methyl-styryl)-4,5-di-hydro-1H-pyrazol-1-yl]-6-(thio-phen-2-yl)-4-(tri-fluoro-meth-yl)pyrimidine chloro-form monosolvate.

In the crystal structure of the title compound, C28H23F3N4S·CHCl3, the chloro-form solvate mol-ecules connect the pyrimidine mol-ecules into chains along [101] through weak C-H⋯N and C-H⋯Cl hydrogen-bond inter-actions. There are further connections between adjacent chains through F⋯Cl halogen contacts of 3.185 (3) Å, with the -CF3 group presenting a significant short F⋯F inter-chain distance of 2.712 (4) Å. The five-membered pyrazole ring is approximately planar (r.m.s. deviation = 0.050 Å). The pyrimidine ring makes dihedral angles of 84.15 (8) and 4.56 (8)° with the benzene rings.

2-(5-Chloro-2-oxoindolin-3-yl-idene)hydrazinecarbo-thio-amide.

The title mol-ecule, C9H7ClN4OS, is almost planar, with an r.m.s. deviation of 0.034 (2) Šfor the mean plane through all the non-H atoms. Intra-molecular N-H⋯O and N-H⋯N hydrogen bonds form S(6) and S(5) ring motifs, respectively. In the crystal, mol-ecules are assembled into inversion dimers through pairs of co-operative N-H⋯Cl inter-actions. These dimers are connected along the b axis by N-H⋯O and N-H⋯S hydrogen bonds, generating layers parallel to (103). The layers are further connected along the a axis into a three-dimensional network, through weak π-π stacking inter-actions [centroid-centroid distance = 3.849 (2) Å].

(S,Z)-3-Phenyl-2-[(1,1,1-tri-chloro-7-meth-oxy-2,7-dioxohept-3-en-4-yl)amino]-propanoic acid monohydrate.

In the title compound, C17H18Cl3NO5·H2O, intra-molecular N-H⋯O and C-H⋯Cl hydrogen bonds form S(6) and S(5) ring motifs, respectively. The chiral organic mol-ecule is connected to the solvent water mol-ecule by a short O-H⋯O hydrogen bond. In the crystal, a weak C-H⋯Cl inter-action connects the organic mol-ecules along [100] while the water mol-ecules act as bridges between the organic mol-ecules in both the [100] and [010] directions, generating layers parallel to the ab plane.

2,2'-Dihydroxy-N,N'-(ethane-1,2-di-yl)di-benzamide.

The asymmetric unit of the title compound, C(16)H(16)N(2)O(4), contains one half-mol-ecule, the whole mol-ecule being generated by an inversion center located at the mid-point of the C-C bond of the central ethane group. An intra-molecular O-H⋯O hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are connected via N-H⋯O hydrogen bonds, generating infinite chains along [1-10].