Since last century, peptides have emerged as potential drugs with >90 FDA approvals for various targets with several in the pipeline. Sulphur, in peptides is present either as thiol (-SH) from Cys or ...thioether from Met. In this review, all the peptides approved by FDA since 2000 containing sulphur have been included. Among them ∼50 % contains disulphide bridges. This clearly demonstrates the significance of disulphide bonds in peptide drugs. This can be achieved synthetically by using orthogonal protecting groups (PGs) for –SH. These PGs are compatible with Solid Phase Peptide Synthesis (SPPS), which is still the method of choice for peptide synthesis. The orthogonal PGs used for Cys thiol side chain protecting for disulphide bond formation have been included which are currently in use both by academia and industry from small scale to large scale synthesis. In addition, the details of the FDA approved drugs containing Cys and Met (or both) have also been discussed.
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•50 % of FDA approved peptides containing sulphur.•Total 26 peptide drugs have been approved since 2000 which contains sulphur as disulphide, thioether and thiophene.•Toolkit of cysteine orthogonal protecting groups used in Peptide Synthesis.•ADCs bioconjugation with linker is via thiol which comes from Cys of antibody.
Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin-benzimidazole hybrids were designed, ...synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzodimidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl)-2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. In addition, it has showed no cytotoxicity and hemolysis at 10 times the MIC concentration. SAR studies indicate that position of the chlorine atom in the hybrid critically determines the antibacterial activity.
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Respiratory infections resulting from pulmonary inflammation emerging as a leading cause of death worldwide. However, only twenty-seven new drugs were approved in the last five ...decades. In this review, we presented synthetic approaches for twenty-seven FDA-approved medications used to treat asthma and chronic obstructive pulmonary diseases (COPD), along with their mode of action.
Antiulcer activity of novel quinoline-chalcone hybrids (13–37) was investigated. Among them, eight compounds (14, 16, 17, 23, 29, 31, 32 and 35) were found to be active in various ulcer models in ...Sprague–Dawley (SD) rats. To understand the mechanism of action of these hybrids, the effects of the compounds on antisecretory and cytoprotective activities were studied. All these active hybrids improved the depleted levels of mucin and consequently inhibited the formation of erosions in a pyloric ligated ulcer model. In addition, they also significantly increased the gastric PGE2 content in an aspirin induced ulcer model. The additional experiments including the in vitro metabolic stability and in vivo pharmacokinetics led to the identification of compound 17 as an orally active and safe candidate that is worthy of further investigation to be developed as an antiulcer agent.
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•A series of quinoline-chalcone hybrids were designed and synthesized.•Hybrids were evaluated in various ulcer models in Sprague–Dawley (SD) rats.•The hybrids 14, 16, 17, 23, 29, 31, 32 and 35 showed significant gastroprotection.•The cytoprotective effect of lead hybrid 17 was established.
Hit, Lead & Candidate Discovery
Drug repurposing has become a recent trend in drug development programs, where previously developed drugs are explored for hit and redeveloped into potential ...therapeutic agents for new diseases. Globally, in any drug development program, a series of molecules are synthesized and evaluated for the hypothesized activity. Hits are developed into lead molecules or drugs, whereas the negative ones are shelved in the lab with no immediate use. We in this project took the previously sidelined small chemical molecules to the next level of utility, where previously developed in‐house small molecules library are tested for the unexplored biological relevant activity. As biofilm formation and quorum sensing play a vital role in bacterial pathogenesis, we believe that they could be one of the most effective targets for antimicrobial agents. In this study, we report the evaluation of 50 different compounds for anti‐biofilm and anti‐quorum sensing activity against Pseudomonas aeruginosa. Out of the screened compounds, three hydrazine‐carboxamide hybrid derivatives showed promising anti‐biofilm property and inhibition of pyocyanin production without any direct antimicrobial activity and cytotoxicity issues. Hydrazine‐carboxamide hybrids can be a new class and promising leads for further anti‐biofilm and anti‐virulence development against microbial infections.
In an attempt to synthesise new tyrosinase inhibitors, we designed and synthesised a series of chalcone-hydroxypyridinone hybrids as potential tyrosinase inhibitors adopting strategic modifications ...of kojic acid. All the newly synthesised compounds were characterised by NMR and mass spectrometry. Initial screening of the target compounds demonstrated that compounds
,
, and
had relatively strong inhibitory activities against tyrosinase monophenolase, with IC
values of 3.07 ± 0.85, 2.25 ± 0.8 and 2.75 ± 1.19 μM, respectively. The inhibitory activity against monophenolase was 6- to 8-fold higher than that of kojic acid. Compounds
,
, and
also showed inhibition of diphenolase, with IC
values of 17.05 ± 0.07, 11.70 ± 0.03 and 19.3 ± 0.28 μM, respectively. The inhibition kinetics of diphenolase indicates that compounds
and
induce reversible inhibition on tyrosinase. Finally, we found that copper coordination should be one of the important inhibitory mechanism of these compounds in tyrosinase.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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The design and synthesis of a series of pyrazolo3,4-dpyrimidinones containing fibrate side chains have been accomplished by utilizing the concept of molecular hybridization. All the ...synthesized compounds were evaluated for the glucose uptake stimulatory effect in L6 rat skeletal muscle cells. Four compounds (3f, 3g, 3j and 3q) were found to show significant stimulation of glucose uptake. Further these four compounds have been examined for their Glut4 translocation stimulatory effect in L6-Glut4myc myotubes. Compound 3q was found to exert maximum increase in GLUT4myc translocation.
Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug-like ...properties. Here, we report synthesis and discovery of a novel small-molecule inhibitor of PP2A-β-catenin signaling that limits both
tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug-like properties of the molecule. Inhibiting PP2A and β-catenin interaction by selectively engaging PR55α-binding site, our most potent small-molecule inhibitor diminished the expression of active β-catenin and its target proteins c-Myc and Cyclin D1. Furthermore, it promotes robust E-cadherin upregulation on the cell surface and increases β-catenin-E-Cadherin association, which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug-like molecule to differentially target β-catenin functionality via interacting with a particular subunit of PP2A.
.
In this study, we presented rational designing and synthesis of coumarin-dihydroquinazolinone conjugates to evaluate their agonist activity at GPR109a receptor. Among the synthesized small molecule ...library, compound 10c displayed robust agonist action at GPR109a with EC50 < 11 nM. Homology model of human GPR109a protein was generated to realize the binding interaction of the active molecule with the active site of GPR109a. Further, the efficacy of active compound 10c was supported by in-vivo experiments which showed reduced body weight in diet induced obese mice model. Interestingly, compound 10c reduced leptin in blood plasma and total serum cholesterol. These results suggest that the coumarin-dihydroquinazolinone conjugate is a suitable scaffold to further expand the chemical diversity and make them potential niacin receptor 1 agonist.
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•Compounds 10c exhibited GPR109a receptor agonist activity (EC50 = 10.6 nM).•Chronic treatment with 10c significantly decreased body weight gain in obese mice.•Treatment of 10c increased leptin sensitivity in obese mice.•Compounds 10c modestly decreased total cholesterol level in obese mice.
In our continuing search for safe and efficacious antifilarials, a series of novel chalcone-benzothiazole hybrids have been synthesized and evaluated for their Brugia malayi thymidylate kinase ...(BmTMK) enzyme inhibition activity. Their selectivity towards BmTMK was studied and compared to the human TMK (HsTMK) by an in silico method. Out of seventeen derivatives, compounds 34 and 42 showed higher interactions with the BmTMK active site. MolDock docking model revealed the interactions of these two derivatives and the results corroborated well with their in vitro antifilarial activities. Our studies suggest that these hybrids are selective towards the BmTMK enzyme and may serve as potential therapeutic agents against filariasis.
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•Discovery of chalcone-benzothiazole hybrids as novel class of BmTMK inhibitors.•Compounds 34 and 42 showed significant inhibition towards BmTMK enzyme.•Results corroborated well with molecular docking against a calculated model of BmTMK.
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