Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary MRSA Infections

Chronic pulmonary MRSA disease in cystic fibrosis (CF) has a high probably of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA but also against protected colonies of MRSA both in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides were synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro with several compounds being 30-60 times more potent than vancomycin. Several compounds were advanced into in vivo nose-only inhalation PK evaluations in rats where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48-h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

Synthesis and Physicochemical Properties of 2,7-Disubstituted Phenanthro[2,1-b:7,8-b’]dithiophenes

We report the design, synthesis, and physicochemical properties of an array of phenanthro[2,1-b:7,8-b’]dithiophene (PDT-2) derivatives by introducing five types of alkyl (CnH2n+1; n = 8, 10, 12, 13, and 14) or two types of decylthienyl groups at 2,7-positions of the PDT-2 core. Systematic investigation revealed that the alkyl length and the type of side chains have a great effect on the physicochemical properties. For alkylated PDT-2, the solubility was gradually decreased as the chain length was increased. For instance, C8-PDT-2 exhibited the highest solubility (5.0 g/L) in chloroform. Additionally, substitution with 5-decylthienyl groups showed poor solubility in both chloroform and toluene, whereas PDT-2 with 4-decylthienyl groups resulted in higher solubility. Furthermore, UV-vis absorption of PDT-2 derivatives substituted by decylthienyl groups showed a redshift, indicating the extension of their π-conjugation length. This work reveals that modification of the conjugated core by alkyl or decylthienyl side chains may be an efficient strategy by which to change the physicochemical properties, which might lead to the development of high-performance organic semiconductors.

Synthesis and Thermal Characteristic of Liquid Crystalline Polyoxetane Containing Trans-Stilbene Side Group

A series of fourteen liquid crystalline monomers and polyoxetanes containing trans-biphenyl side group have been successfully synthesized. The thermal and mesomorphic properties of monomers (1M~14M) and polymers (1P~14P) are measured using DSC, POM, and X-ray. All of the series monomers present enantiotropic smectic H and smectic G phase and the series polymers show enantiotropic smectic A phase which three polymers contained exhibit smectic E. Polyoxetanes have been used as a cationic ring-opening polymerization of oxetane monomers bearing a pendant trans-stilbene mesogenic unit including different spacer length and terminal alkyl length.

New Chloramphenicol Derivatives from the Viewpoint of Anticancer and Antimicrobial Activity

Over the last years, we have been focused on chloramphenicol conjugates that combine in their structure chloramphenicol base with natural polyamines, spermine, spermidine and putrescine, and their modifications. Conjugate 3, with spermidine (SPD) as a natural polyamine linked to chloramphenicol base, showed the best antibacterial and anticancer properties. Using 3 as a prototype, we here explored the influence of the antibacterial and anticancer activity of additional benzyl groups on N1 amino moiety together with modifications of the alkyl length of the aminobutyl fragment of SPD. Our data demonstrate that the novel modifications did not further improve the antibacterial activity of the prototype. However, one of the novel conjugates (4) showed anticancer activity without affecting bacterial growth, thus emerging as a promising anticancer agent, with no adverse effects on bacterial microflora when taken orally.