First Total Synthesis of Gliomasolide C and Formal Total Synthesis of Sch-725674

Syntheses of two 14-membered macrolides Sch-725674 and Gliomasolide C are described here. The first total synthesis of Gliomasolide C, the short synthesis of Sch-725674, and regioselective Wacker oxidation of internal olefin are the highlights of this disclosure. In addition, a key macrocycle with orthogonal functionalities was designed and synthesized on a gram scale for the generation of analogues

High Yielding, Multigram-Scale Synthesis of TBAJ-876 Fragment, 876A-B

TBAJ-876 is an anti-tuberculosis drug shown to have high activity against multi-drug resistant tuberculosis (TB). We report a very efficient synthesis of the TBAJ-876 fragment 876A-B using an aldol condensation strategy starting from 6-bromo-3,4-dihydroquinolin-2(H)-one. The synthesis has been accomplished at multigram scale without the need of chromatography purification steps

Identification and Synthesis of Mycalol Analogues with Improved Potency against Anaplastic Thyroid Carcinoma Cell Lines

The marine metabolite mycalol (<b>1</b>) has a specific inhibitory activity on cells of anaplastic thyroid carcinoma (ATC), a very aggressive and rare cancer that does not have effective conventional therapy. In this study, we describe six new related analogues (<b>2</b>–<b>7</b>) that differ in the length of the terminal alkyl residue and the presence of acetate or 3<i>S</i>-hydroxybutyrate (3S)-3HB as a substituent at C-19. Despite the structural analogies, some of the new members were significantly more cytotoxic than <b>1</b> on cell lines derived from human ATC. Structures inclusive of the 2′<i>R</i>,3<i>R</i>,4<i>S</i>,7<i>R</i>,8<i>S</i>,19<i>R</i> absolute configuration were assigned to <b>2</b>–<b>7</b> on the basis of detailed spectroscopic analysis, synthesis of different isomers, and application of ECD and Mosher’s methods. This work led to the identification of mycalol-578 (<b>3</b>) as the most potent analogue, with an IC₅₀ of 2.3 μM on FRO cells

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication

Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders

Highly Regioselective Protecting-Group-Free Synthesis of the Antimalarial Drug MMV693183

MMV693183 is a promising antimalarial drug candidate that works for uncomplicated malaria treatment and resistance management. Herein, we report an efficient and highly regioselective synthesis of MMV693183. This novel synthetic method highlights a three-step route with an overall yield of 46% from readily available starting materials. The key to the success lies in (1) utilizing the subtle difference of the two amino groups in the starting material (S)-propane-1,2-diamine dihydrochloride without amino protection and (2) identifying the L-(+)-tartaric acid as the counter acid for the organic salt formation, yielding the desired regioisomer up to 100:0. The efficient and scalable three-step protocol operates under mild conditions with a high chemo/regioselectivity, providing effective access to MMV693183