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A series of natural alcohols motif containing novel substituted cinnamates were developed and screened against five bacterial strains namely, Enterococcus faecal (E. faecalis), Escherichia coli (E. coli), Bacillus subtilis (B. subtilis), Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumonieae (K. pneumonieae). Among all cinnamates, YS17 was identified with 100% bacterial growth inhibition across the panel, except in E. faecalis with MIC values of 0.25 mg/mL against B. subtilis and P. aeruginosa whereas 0.125, 0.5 and 1 mg/mL against E. coli, K. pneumonieae and E. faecalis, respectively. The growth inhibitory property of YS17 was further validated by disk diffusion, synergistic study and in vitro toxicity assays. Interestingly, YS17 exhibits synergistic effect in combination with the standard drug Ampicillin (AMP). The single crystal structure analysis of YS4 and YS6 was also performed which reconfirmed their proposed structures. Molecular docking visualized significant non-covalent interactions between E. coli MetAP and YS17 and the structural and conformational changes were further analysed using MD simulation studies. Overall, the study provided a suitable core for further synthetic alterations for their optimization as an antibacterial agent. Communicated by Ramaswamy H. Sarma

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

Novel group of phenoxy-substituted enediyne-triazole conjugates were synthesized by Huisgen [3+2] cycloaddition reaction (Click chemistry) in aqueous media. It was observed that enediynes were stable in aqueous medium and open-air conditions.

To combat the emergence of drug resistance against the existing antimalarials, novel side chain containing 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) were designed and synthesized by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1- yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4- azido-7-chloroquinoline, respectively via a ‘click’ reaction. The selected CQTrICh-analogs: 7l and 7r inhibited chloroquine-sensitive (3D7) and resistant (RKL-9) strains of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed insignificant hemolysis and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. Given the importance of Calcium-Dependent Protein Kinase 1 (PfCDPK1) in the parasite biology, notably during late schizogony and subsequent invasion of merozoites into host RBCs, we identified this protein as a possible molecular target of these active hybrids. In silico interaction analysis indicated that 7l and 7r stably interact with the catalytically active ATP-binding pocket of PfCDPK1, by the formation of energetically favorable H-bonds. Furthermore, in vitro Microscale Thermophoresis and kinase assays with recombinant PfCDPK1 demonstrated that the active hybrids interact with and inhibit the kinase activity, thus presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating that they are selective for the parasite kinase. Conceivably, we report the antiplasmodial potential of novel kinase targeting bio-conjugates, a step towards developing pan-kinase inhibitors, which is a prerequisite for cross-stage anti-malarial protection.GRAPHICAL ABSTRACT

The side-chains of quinoline antimalarial agents are the major concern of focus to build novel and efficaciaous bioactive and clinical antimalarials. Bioative antimalarial analogs may play a critical role in pH trapping in the food vacuole of RBC’s with the help of fragmented amino acid, thus lead to β-hematin inhibition. Here, the authors tried to summarize a useful, comprehensive compilation of side-chain modified ACQs along with their synthesis, biophysical and therapeutic applications etc. of potent antiplasmodial agents and therefore, opening the door towards the potential clinical status.

Abstract: Apicomplexian parasite of the genus Plasmodium is the causative agent of malaria, one of the most devastating, furious and common infectious disease throughout the world. According to the latest World malaria report, there were 229 million cases of malaria in 2019 majorly consist of children under 5 years of age. Some of known analogues viz. quinine, quinoline-containing compounds have been used for last century in the clinical treatment of malaria. Past few decades witnessed the emergence of multi-drug resistance (MDR) strains of Plasmodium species to existing antimalarials pressing the need for new drug candidates. Thus, in those decades bioorganometallic approach to malaria therapy has been introduced which led to the discovery of noval metalcontaining aminoquinolines analogues viz. ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metalanalogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aim to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amonoquines.

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

Plectranthus is known for its medicinal value . The paper describes the antibacterial and cytotoxic activity of diterpenoids ent -7-hydroxykaur-15,16-en-19-oic acid (1), 17-oxokaur-15,16-en-19-oic acid (2) and ent-7-hydroxy-15,16-epoxykauran-19-oic acid (3), isolated from the shade-dried and powdered leaves of Indian Plactranthus coesta. Diterpenoid 3 was isolated for the first time from Indian P. coesta . Diterpenoid 1, shows potent activity against E. coli (15.6 µg/mL), P. aureginosa (17 µg/mL) and K. planticola (32.5 µg/mL), while diterpenoid 2, also showed good activity against E. coli (61 µg/mL), P. aureginosa (61 µg/mL), K. planticola (61 µg/mL) and S. epidermidis (125 µg/mL). Diterpenoids 1-3 were found to be more efficacious on U87 cancer cells and less toxic on normal human HEK and HeLa cells.

A novel group of symmetrical and asymmetrical acyclic enediynes has been synthesized by using Sonogashira coupling conditions and characterized spectroscopically. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

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.

Syntheses and antibacterial activity of 13-membered 1,3-phendioxy substituted cyclic enediynes are reported. The compounds were screened against gram-positive and gram-negative strains and some of the compounds exhibit potent antibacterial activity.

A convenient method for the synthesis of symmetrically and asymmetrically substituted acyclic enediynes has been developed using microwave irradiation. The reaction completes in 3-5 minutes, while same reaction takes 14-18 h to complete under conventional heating method.

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 group of O-, N-, and S-substituted symmetrical and asymmetrical acyclic enediynes are obtained under Sonogashira coupling conditions.

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.

The enediynes are known for highly potent anticancer, antimicrobial, as well as cytotoxic activities. The discovery of enediynes from natural sources was achieved in late 1980s. They are presently of high interest, because they exert their biological action due to their ability to form a diradical, which abstracts H-atoms from the DNA backbone, thus causing cell death. Nowadays, the major works are dedicated to the syntheses of enediynes. This review covers recent developments in enediyne chemistry of the last few decades. It is subdivided in six chapters dealing with the discussion of the chemistry and biological significances of enediynes, and the factors responsible for a better activation of enediynes and potent biological evaluations.

The enediynes are known for highly potent anticancer, antimicrobial, as well as cytotoxic activities. The discovery of enediynes from natural sources was achieved in late 1980s. They are presently of high interest, because they exert their biological action due to their ability to form a diradical, which abstracts H-atoms from the DNA backbone, thus causing cell death. Nowadays, the major works are dedicated to the syntheses of enediynes. This review covers recent developments in enediyne chemistry of the last few decades. It is subdivided in six chapters dealing with the discussion of the chemistry and biological significances of enediynes, and the factors responsible for a better activation of enediynes and potent biological evaluations.

Fifteen novel cyclic enediynes are prepared by using a simple and straightforward approach.

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.

We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple and straightforward approach. Representative examples were screened for their anticancer activities on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne derivatives with halogen substitutions, especially fluorides were found to be active against most of the cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for several cell lines, which shows the potential of these class of compound towards anticancer application.