Synthesis, conformational analysis and biological studies of cyclic cationic antimicrobial peptides containing sugar amino acids

Sugar amino acid based 24-membered macrocyclic C2-symmetric cationic peptides were designed and synthesized. The cationic group was introduced in the sugar amino acids. The conformation of these cyclic compounds was ascertained through NMR techniques, which proved they were amphipathic in nature. All the compounds were bacteriolytic, showed good activity against the Gr(+ve) and Gr(-ve) bacteria, and exhibited low hemolytic activity.     

Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)

Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis.     

Synthesis and Antimicrobial Activity of Linked Heterocyclics Containing Pyrazole and Oxadiazoles

A new series of 3‐(arylaminomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thiones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j has been synthesized by the reaction of 5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐1,3,4‐oxadiazol‐2‐ylhydrosulfide 5 with formaldehyde and corresponding anilines. The chemical structures of newly synthesized compounds were elucidated by IR, ¹H, ¹³C‐NMR, MS, and elemental analyses. The compounds 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j were evaluated for their antibacterial activity against three representative Gram positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11) and Staphylococcus aureus (MTCC 96), and three Gram negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella aerogenes (MTCC 39) and Chromobacterium violaceum. Among the screened 6b , 6d , 6i , and 6j in which oxadiazole moiety bearing 4‐fluoroanilinomethyl, 4‐chloroanilinomethyl, 2‐trifluoromethylanilinomethyl, and 2,5‐difluoroanilinomethyl groups, respectively, showed high activity against all the microorganisms used. In addition these compounds were also screened for their antifungal activity against four fungal organisms viz. Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Most of these new compounds showed appreciable activity against test fungi, and emerged as potential molecules for further development.     

The Reductive Leaching of Chalcopyrite by Chromium(II) Chloride for the Rapid and Complete Extraction of Copper

A hydrometallurgical process is developed to lower the costs of copper production and thereby sustain the use of copper throughout the global transition to renewable energy technologies. The unique feature of the hydrometallurgical process is the reductive treatment of chalcopyrite, which is in contrast to the oxidative treatment more commonly pursued in the literature. Chalcopyrite reduction by chromium(II) ion is described for the first time and superior kinetics are shown. At high concentrate loadings of 39, 78, and 117 g L⁻¹, chalcopyrite reacted completely within minutes at room temperature and pressure. The XRD, SEM-EDS, and XPS measurements indicate that chalcopyrite reacts to form copper(I) chloride (CuCl). After the reductive treatment, the mineral products are leached by iron(III) sulfate to demonstrate the complete extraction of copper. The chromium(II) ion may be regenerated by an electrolysis unit inspired by an iron chromium flow battery in a practical industrial process.