A series of aryl-functionalized and ferrocenyl monothiosemicarbazone compounds (L1-L4) were synthesized in moderate yields via a general Schiff-base condensation reaction. The thiosemicarbazone (TSC) ligands were reacted with the ruthenium dimer [Ru(Ar)(μ-Cl)Cl](2) (Ar = benzene; p-cymene) to yield a series of cationic mononuclear ruthenium(II)-arene thiosemicarbazone complexes of the general type [Ru(Cl)(TSC)(Ar)]Cl (1-8). The thiosemicarbazone ligands act as bidentate chelating ligands that coordinate to the ruthenium(ii) ion via the imine nitrogen and the thione sulfur atoms. The thiosemicarbazone ligands, as well as their metal complexes, were characterized by NMR, IR spectroscopy and ESI(+)-mass spectrometry. The molecular structure of the mononuclear ruthenium(II)-arene thiosemicarbazone complex (6) was determined by single-crystal X-ray diffraction analysis. The ruthenium(II)-arene thiosemicarbazone complexes were further evaluated for their in vitro antiparasitic activities against the Plasmodium falciparum chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains, as well as the G3 strain of Trichomonas vaginalis.
High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure-activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (ΔcydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.
For the treatment of malaria which affects nearly 200 million people each year and the continued exacerbation by the emergence of drug resistance to most of the available antimalarials, the "covalent bitherapy" suggests hybrid molecules to be the next-generation antimalarial drugs. In this investigation, new hybrids of 4-aminoquinoline and pyrimidine moieties that show antiplasmodial activity in the nM range against chloroquine-resistant as well as chloroquine-sensitive strains of Plasmodium falciparum have been prepared. Cytotoxicity evaluation and mode of action of most potent hybrid molecule have been conducted.
Tridentate cycloplatinated thiosemicarbazone complexes have been prepared from a biologically significant ligand, 3,4-dichloroacetophenone thiosemicarbazone (1). The tetranuclear complex 2 was prepared by reaction of the ligand with K2[PtCl4]. Two mononuclear (3 and 4) and two dinuclear (5 and 6) complexes were isolated upon cleavage of the Pt–Sbridging bonds of the tetranuclear complex 2 with the appropriate phosphane ligand. Each complex was characterized using various analytical and spectroscopic techniques, and the molecular structures of 2–4 were also elucidated. The in vitro antiparasitic activities of these complexes against Plasmodium falciparum strains (D10 (chloroquine sensitive) and Dd2 (chloroquine resistant)) and Trichomonas vaginalis have been determined. Preliminary studies into their potential plasmodial target in the form of β-hematin formation inhibition assays were also completed. Preliminary results suggest that ligand 1 and complex 3 do not hinder formation of β-hematin. The antiproliferative activity of the complexes against the cisplatin-senstive A2780 and cisplatin-resistant A2780cisR human ovarian cancer cell lines has been evaluated. The complexes were found to exhibit moderate to weak inhibitory activities.
Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity.
Our study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with non-syndromic childhood hearing impairment (HI) as well as the environmental causes of HI in Ghana. Medical reports of 1,104 students attending schools for the deaf were analyzed. Families segregating HI, as well as isolated cases of HI of putative genetic origin were recruited. DNA was extracted from peripheral blood followed by Sanger sequencing of the entire coding region of GJB2. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of GJB6-D3S1830 deletion. Ninetyseven families segregating HI were identified, with 235 affected individuals; and a total of 166 isolated cases of putative genetic causes, were sampled from 11 schools for the deaf in Ghana. The environmental factors, particularly meningitis, remain a major cause of HI impairment in Ghana. The male/female ratio was 1.49. Only 59.6% of the patients had their first comprehensive HI test between 6 to 11 years of age. Nearly all the participants had sensorineural HI (99.5%; n = 639). The majority had pre-lingual HI (68.3%, n = 754), of which 92.8% were congenital. Pedigree analysis suggested autosomal recessive inheritance in 96.9% of the familial cases. GJB2-R143W mutation, previously reported as founder a mutation in Ghana accounted for 25.9% (21/81) in the homozygous state in familial cases, and in 7.9% (11/140) of non-familial non-syndromic congenital HI cases, of putative genetic origin. In a control population without HI, we found a prevalent of GJB2-R143W carriers of 1.4% (2/145), in the heterozygous state. No GJB6-D3S1830 deletion was identified in any of the HI patients. GJB2-R143W mutation accounted for over a quarter of familial non-syndromic HI in Ghana and should be investigated in clinical practice. The large connexin 30 gene deletion (GJB6-D3S1830 deletion) does not account for of congenital non-syndromic HI in Ghana. There is a need to employ next generation sequencing approaches and functional genomics studies to identify the other genes involved in most families and isolated cases of HI in Ghana.
Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.
Two silicon-containing analogues (1, 2) of chloroquine, modified in the lateral side chain with organosilicon moieties, were synthesized. Compounds 1 and 2 were further reacted with dinuclear half-sandwich transition metal precursors [Ru(Ar)(μ-Cl)Cl]2 (Ar = η6-p-iPrC6H4Me; η6-C6H6; η6-C6H5OCH2CH2OH), [Rh(COD)(μ-Cl)]2, and [RhCp*(μ-Cl)Cl]2, to yield a series of neutral mononuclear Ru(II), Rh(I), and Rh(III) silicon-aminoquinoline complexes (3–12). Compounds 1 and 2 act as monodentate donors that coordinate to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. All the compounds were characterized using various analytical and spectroscopic techniques, and the molecular structures of compounds 2 and 11 were elucidated by single-crystal X-ray diffraction analysis. Furthermore, the in vitro pharmacological activities of compounds 1–12 were established against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malarial parasite Plasmodium falciparum and against the pathogenic bacterium Mycobacterium tuberculosis H37Rv, as well as an esophageal (WHCO1) cancer cell line.
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