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In this work, substituted 1,2,4-oxadiazoles (OX1− OX27) were screened against five bacterial strains, identified to be OX7 and OX11 as growth inhibitors with minimum inhibitory concentration (MIC) values of 31.25 and 15.75 μg/mL, respectively. The growth inhibitory property of OX7 and OX11 was further validated by disk diffusion, growth curve, and time kill curve assays. Both disrupted biofilm formation with 92−100% reduction examined by the XTT assay were further visualized by scanning electron microscopy analysis. These compounds in combination with ciprofloxacin also exhibit synergy against Escherichia coli cells. With insignificant cytotoxic behavior on HEK293 cells, human red blood cells, and Galleria mellonella larvae, OX11 was tested against 28 multidrug resistant environmental isolates of bacteria and showed inhibition of Kluyvera georgiana and Citrobacter werkmanii strains with 32 and 16 μg/mL MIC values, respectively. The synergistic behavior of OX11 with ampicillin showed many fold reductions in MIC values against K. georgiana and Klebsiella pneumoniae multidrug resistant strains. Further, transmission electron microscopy analysis of OX11-treated E. coli cells showed a significantly damaged cell wall, which resulted in the loss of integrity and cytosolic oozing. OX11 showed significant changes in the secondary structure of human serum albumin (HSA) in the presence of OX11, enhancing HSA stability. Overall, the study provided a suitable core for further synthetic alterations and development as an antibacterial agent

Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) P. falciparum strains with 5/6 having IC50 < 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in P. berghei infected mice in 3/6 derivatives following oral dosing at 4 × 30 ...

Chloroquine (CQ) analogues are the most important scaffolds used as an anti-malarial drug, and helping human world to control and eradicate malaria for decades. Biologically, it is expected that CQ is selectively deposited in the food vacuole of the parasite, and exerting its antimalarial effect by preventing the polymerization of the toxic heme. Researchers are involved in synthesizing a number of CQ analogues to overcome its drug-resistance properties but still the toxicity has been a major problem with many of them. Nevertheless, the question of whether this problem can be overcome remains of great interest. Our vision is thus to continue with this approach, we have synthesized more hydrophilic derivatives which are likely to be less toxic 4-aminosubstituted-7-chloroquinolines analogous. Our previous experience says that the production of this class of compounds is not a problem, but purification of these quinoline analogues are very challenging. After synthesizing a series of more hydrophilic derivatives which were biologically potent, we have synthesized a series of Chloro- and Cyano- substituted quinoline-triazole conjugates and other lipophilic antimalarial scafolds in competitive yield. These quinoline-triazole analogues were showing good to moderate In vitro antimalarial activity against P. falciparum (CQS-10 & CQR-K1 strain) and also showing β-haematin inhibition activity. For synthesizing quinoline-triazole conjugates, we have synthesized amine-triazole counterpart first and then coupled with the 4,7-Dichloro or 4-Chloro-7-Cyano-quinoline. These compounds are well characterized by NMR, mass, IR and other analytical tools. These compounds will be submitted for testing against CYP3A4, an enzyme important in drug metabolism inhibition which is often related to adverse drug effects and for hERG liability. In vitro antimalarial activity will be measured in chloroquine sensitive and resistant P. falciparum and drug metabolism tested in mice. At the same time association with Fe(III)PPIX and β-haematin inhibition and then that you will be testing various biological properties in the future. References: J. Egan, R. Hunter, C. H. Kaschula, H. M. Marques, A. Misplon, J. C. Walden, J. Med. Chem. 2000, 43, 283 H. Kaschula, T. J. Egan, R. Hunter, N. Basilico, S. Parapini, D. Tarameli, E. Pasini, D. Monti, J. Med. Chem. 2002, 45, 3531. J. Egan, K. R. Koch, P. L. Swan, C. Clarkson, D. A. V. Schalkwyk, P. J. Smith, J. Med. Chem. 2004, 47, 2926. Zhishiri, M. C. Joshi, R. Hunter, K. Chibale, P. J. Smith, R. L. Summers, R. E. Martin, T. J. Egan, J. Med. Chem. 2011, 54(19), 6956-6968. C. Joshi, K. J. Wicht, D. Taylor, R. Hunter, P. J. Smith, T. J. Egan, Eur. J. Med. Chem. 2013, 69, 338-347

Phytochemical constituents isolated from Indian species of the genus Plectranthus reported up to 2009 are compiled. In India, the genus Plectranthus is found in all the habitats and altitudes, particularly in the Himalaya, the Southern Ghats, and the Nilgiri region. P. amboinicus, P. barbatus, P. caninus, P. mollis, P. coetsa, and P. incanus are the most common species found in India. Phytochemical studies of the genus revealed that Indian Plectranthus species are rich in essential oil, and that the most abundant secondary metabolites are diterpenoids, i.e., labdanes, abietanes, and ent-kauranes, as well as triterpenoids.

Advances in the sophisticated instruments for the isolation and characterization of marine natural products, and development in the biological assay systems, have resulted in the discovery of various compounds of biomedical application. Marine natural products have been a source of new leads for the treatment of many deadly diseases such as cancer, acquired immuno-deficiency syndrome (AIDS) etc. The compounds of marine origin are diverse in structural class from simple linear peptides to complex macrocyclic polyethers. Number of marine peptides have been isolated in recent years which exhibit potent biological activities, and many of the compounds showed promising anticancer activity. Didemnin was the first marine peptide that entered in human clinical trials in US for the treatment of cancer, and other anticancer peptides such as kahalalide F, hemiasterlin, dolastatins, cemadotin, soblidotin, didemnins and aplidine have entered in the clinical trials. Clinical status of anticancer marine derived pep tides have been discussed and reviewed.

A novel series of quinoline triazole amide analogues ( 38 – 51 ) has been synthesized. Analogues 38 – 44 had a Cl substituent at the 7-position of the quinoline ring, while 45 – 51 had a CN substituent at this position. Compounds 40 , 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC 50 values in the range of 349–1247 nM, with 40 and 45 , but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38 – 44 exhibited a strong linear dependence of log(1/IC 50 ) on log P . Thus, the more lipophilic, the more active it was found be. The 7-CN series 45 – 51 showed no such dependence. The resistance index (IC 50 K1/IC 50 D10) also exhibited a linear dependence on log P , with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.

A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC(50) value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.

Phytochemical constituents isolated from Indian species of the genus Plectranthus reported up to 2009 are compiled. In India, the genus Plectranthus is found in all the habitats and altitudes, particularly in the Himalaya, the Southern Ghats, and the Nilgiri region. P. amboinicus, P. barbatus, P. caninus, P. mollis, P. coetsa, and P. incanus are the most common species found in India. Phytochemical studies of the genus revealed that Indian Plectranthus species are rich in essential oil, and that the most abundant secondary metabolites are diterpenoids, i.e., labdanes, abietanes, and ent-kauranes, as well as triterpenoids.