Medicinal Chemistry - Volume 17, Issue 1, 2021

Background: Citral is one of the main components of lemongrass oil present at a concentration of 65-85% approximately and is generally separated by steam refining. It is an important component in the manufacturing of scents, citrus chemicals, cosmetics, food and pharmaceutical products. Objectives: This article aims at reviewing the published literature to highlight the metabolism, extraction strategies and therapeutic significance of citral for improving the scope of its application in the food and pharma industry. Discussions: Apart from steam refining, there are other techniques like solvent extraction, supercritical fluid extraction and ultrasonication by which citral can be extracted and the method of extraction defines its quality. It is an unstable molecule and undergoes rapid deterioration on exposure to air. Citral is biosynthesized by the plants through the 5 carbon precursor isopentenyl diphosphate (IPP) units utilizing two diverse biochemical pathways, acetate– mevalonate (acetate– MVA) pathway or 2C-methylerythritol-4-phosphate (MEP). Orally Citral was absolutely digested in the gastrointestinal tract and its metabolism leads to the discharge of metabolites which include a number of acids and a biliary glucuronide. There is no scientific evidence about the long term bioavailability of citral in the body and it has no adverse effect on tissue related to its accumulation and delayed excretion. Citral exhibits various important therapeutic properties like antimicrobial, antioxidant, anticancer, anti-diabetic and anti-inflammatory. Conclusion: Citral is a potent biomolecule with various important biological activities and therapeutic implications. Strategies are required to increase the stability of citral which could increase its applications.

Background: Benzazole and coumarin derivatives are one of the most privileged heterocyclic substructures in the medicinal chemistry with well-known biological features, which include a wide range of versatile biological activities as well as excellent spectroscopic characteristics thus offering their potential application in many research fields. Objective: The prepared iminocoumarins were synthesized to evaluate their antioxidative potential by using ABTS and FRAP assays and in vitro antiproliferative activity. Methods: A series of coumarin derivatives containing a 2-benzazole motif were synthesized and evaluated for their antioxidative capacity and antiproliferative activity. Their molecular structure incorporates a push-pull functionality: an electron donor donating group at the 7-position with an electron-withdrawing group, such as benzimidazole, benzothiazole and imidazopyridine fragment at the 3-position. Results: The iminocoumarins bearing different substituents on 7-position were evaluated for their antiproliferative activity on tree cancer cells with only 4 compounds showing the antiproliferative activity. The most active derivative was N,N-diethylamino substituted benzimidazole derivative 4d and imidazo[4,5-b]pyridine analogue 6b, both also displayed selective activity toward CEM with submicromolar inhibitory concentration (0.059 μM; 0.17 ± 0.09, respectively). The inhibitory effect of 4d and 6b derivatives on the cell-cycle progression of HeLa cells was studied. A flow cytometric analysis of the HeLa cells indicated an appreciable cell-cycle arrest in a dose-dependent manner. Antioxidant properties were studied by ABTS and FRAP assays and obtained results revealed that the most promising antioxidant has proven to be compound 3b while other compounds, in general, showed moderate to very low antioxidative capacity in both assays. Conclusion: Unsubstituted benzimidazole derivatives bearing hydroxyl group on iminocoumarin nuclei exhibited the most prominent antioxidant potential in ABTS assay (3b; 40.5 ± 0.01). The most significant and selective antiproliferative activity was displayed by compounds 4d and 6b (0.059 μM; 0.17 ± 0.09, respectively), which were chosen as lead compounds for further optimization and rational design to obtain more active and selective antiproliferative agents.

Background: In the last years, many efforts have been made to find colchicine derivatives with reduced toxicity. Additionally, the deregulation of amino acid uptake by cancer cells provides an opportunity to improve anticancer drug effectiveness. Objective: To design new colchicine derivatives with reduced cytotoxicity and enhanced selectivity by means of introducing aminoacyl groups. Methods: 34 colchicine analogues bearing L- and D-amino acid pendants were synthetized and characterized by NMR, IR and MS techniques. Cytotoxicity and antimitotic properties were assessed by spectrophotometry and cell cycle assays. Oncogene downregulation was studied by RTqPCR whereas in vivo studies were performed in SCID mice. Results: Compounds exhibit high antiproliferative activities at the nanomolar level while being, in general, less cytotoxic than colchicine. Most compounds inhibit the polymerization of tubulin in a way similar to colchicine itself, with L-amino acid derivatives being the most active in the inhibition of tubulin polymerization. All selected compounds caused cell cycle arrest at the G2/M phase when tested at 1 μM. More specifically, Boc-L-proline derivative 6 arrested half of the population and showed one of the highest Selectivity Indexes. Derivatives 1 (Boc-glycine), 27 (D-leucine) and 31 (Boc-glycine-glycine) proved fairly active in downregulating the expression of the c-Myc, hTERT and VEGF oncogenes, with compound 6 (Boc-L-proline) having the highest activity. This compound was shown to exert a potent anti-tumor effect when administered intraperitoneally (LD50 > 100 mg/kg for 6, compared with 2.5 mg/kg for colchicine). Conclusion: Compound 6 offers an opportunity to be used in cancer therapy with less toxicity problems than colchicine.

Background: In the therapy of cancer, several treatments have been designed using nanomaterials, among which gold nanoparticles (AuNPs) have been featured as a promising antitumoral agent. Our research group has developed the synthesis of gold nanoparticles L-AuNPs and D-AuNPs stabilized with zwitterions of imidazolium (L-1 and D-1) derived from L-methionine and D-methionine. Because the stabilizer agent is chiral, we observed through circular dichroism that AuNPs also present chirality; such chirality as well as the fact that the stabilizing agent contains fragments of methionine and imidazolium that are commonly involved in biological processes, opens up the possibility that this system may have biological compatibility. Additionally, the presence of methionine in the stabilizing agent opens the application of this system as a possible antitumor agent because methionine is involved in methylation processes of molecules such as DNA. Objective: The aim of this research is the evaluation of the antitumor activity of gold nanoparticles stabilized with zwitterions of imidazolium (L-AuNPs) derived from L-methionine in the model of BALB/c mice with lymphoma L5178Y. Methods: Taking as a parameter cell density, the evaluation of the inhibitory effect of L-AuNPs was carried out with a series of in vivo tests in BALB/c type mice; three groups of five mice each were formed (Groups 1, 2 and 3); all mice were i.p. inoculated with the lymphoblast murine L5178Y. Group 1 consisted of mice without treatment. In the Groups 2 and 3 the mice were treated with L-AuNPs at 0.3 mg/Kg on days 1, 7 and 14 by orally and intraperitonally respectively. Results: These results show low antitumor activity of these gold nanoparticles (L-NPsAu) but interestingly, the imidazolium stabilizing agent of gold nanoparticle (L-1) displayed promising antitumor activity. On the other hand, the enantiomer of L-1, (D-1) as well as asymmetric imidazole derivate from L-methionine (L-2), do not exhibit the same activity as L-1. Conclusion: The imidazolium stabilizing agent (L-1) displayed promising antitumor activity. Modifications in the structure of L-1 showed that, the stereochemistry (like D-1) and the presence of methionine fragments (like L-2) are determinants in the antitumor activity of this compound.

Purpose: Carbon monoxide-releasing molecules (CORMs) are a special class of organometallic complexes that have been reported to offer beneficial effects against different conditions including several subtypes of cancer. Especially for the aggressive and poorly treated triplenegative breast cancer (TNBC), early CORMs have been shown to diminish malignant angiogenesis and may be considered as an alternative approach. So, this study aimed at testing novel CORM molecules against angiogenesis in TNBC seeking potent drug candidates for new therapies. Methods: Based on previous studies, CORM-3 was chosen as the lead compound and a group of 15 new ruthenium-based CORMs was synthesized and subsequently evaluated in vitro for potential anti-angiogenic properties. Results: A similar anti-angiogenic behaviour to the lead complex was observed and a new CORM, complex 4, emerged as a promising agent from this study. Specifically, this complex offered better inhibition of the activation of VEGFR2 and other downstream proteins of vascular endothelial cells. Complex 4 also retained the ability of the parent molecule to reduce the upregulated VEGF expression from TNBC cells and inhibit endothelial cell migration and new vessel formation. The lack of significant cytotoxicity and the downregulating activity over the cytoprotective enzyme haem oxygenase-1 (HO-1) in cancer cells may also favour CORMs against this poorly treated subtype of breast cancer. Conclusion: Since the anti-angiogenic approach is one of the few available targeted strategies against TNBC, both CORM-3 and the new complex 4 should be considered for further research as combination agents with existing anti-angiogenic drugs for more effective treatment of malignant angiogenesis in TNBC.

Background: Life style and jobs in current situations have generated increased free radicals such as hydroxyl (OH•) and superoxide (O2•) radicals, thereby increasing stress in humans. Interest in search of antioxidants that trap these free radicals has increased to relieve stress. β-carotene (provitamin A), ascorbic acid (vitamin C), tocopherol or vitamin E, Trolox; butyl hydroxy toluene and phenolic compounds are the well-known antioxidants. Several methods evaluate the antioxidant property existing in natural substances (medicinal plants and agri-food products) and synthetic compounds (2-methyl-3- (pyrrolidin-2-ylideneamino) quinazolin-4 (3H) –one and 3,3'- (1,4- phenylenebis (methanylylidene)) bis (azanylylidene) (2-methyl-quinazolin-4 (3H) -one). Objective: The objective of this study is to focus on complexes with p-hydroxycinnamic acids to trap free radicals in a greener way. Methods: Spectroscopic shifts and structural studies were employed to attribute electronic properties responsible for antioxidant profile. Spectroscopic shifts in wavenumbers were attributed with Fourier Transform Infrared Spectra (FTIR) and Fourier Transform Raman spectra (FT Raman Spectra). Structural studies were performed with Gaussian package, electron density method the B3LYP method, basis set 6-31(d) for attributing electronic properties responsible for antioxidant profile. Results: Interpretation of FTIR spectra revealed spectroscopic shifts in wavenumbers in all the complexes responsible for bonding. Further, studies confirmed the formation of complex with reduced intensities in Raman spectra. Computational studies revealed enhancement in molecular and electronic properties responsible for antioxidant power. Conclusion: Studies revealed that complex with p-nitroaniline contribute to greater acceptor and donor power responsible for antioxidant power. These higher powers suggest the best antiradicals to trap free radicals.

Background: Bacterial infections are considered as one of the major global health threats, so it is very essential to design and develop new antibacterial agents to overcome the drawbacks of existing antibacterial agents. Methods: The aim of this work is to synthesize a series of new fluoroquinolone-3-carboxamide amino acid conjugates by molecular hybridization. We utilized benzotriazole chemistry to synthesize the desired hybrid conjugates. Results: All the conjugates were synthesized in good yields, characterized, evaluated for their antibacterial activity. The compounds were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Synthesized conjugates were tested for activity against medically relevant pathogens; Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27856) Staphylococcus aureus (ATCC 25923) and Enterococcus faecalis (ATCC 19433). Conclusion: The observed antibacterial experimental data indicates the selectivity of our synthesized conjugates against E.Coli. The protecting group on amino acids decreases the antibacterial activity. The synthesized conjugates are non-toxic to the normal cell lines. The experimental data were supported by computational studies.

Background: The antimicrobial resistance due to biofilm formation among bacteria is a significant problem in the healthcare and food industries. Objective: The current study describes the synthesis of enrofloxacin derivatives 2-17, and the evaluation of their anti-bacterial and anti-biofilm activities. Methods: Compounds 2-17 were synthesized through the acylation of enrofloxacin with thionyl chloride, followed by reaction with different aromatic amines. The new analogues identified among the sixteen compounds were 2-7, 11, 14, and 17. Results: Compound 2 appeared to be effective against pathogens S. aureus as well as K. pneumonia, whereas, compound 11 was found active against K. pneumonia only. Compound 2 inhibited >75% biofilm formation of S. aureus at 20 μg/mL and K. pneumonia at 10 μg/mL concentrations. These doses are far below the bactericidal concentration of compound 2, suggesting the anti-virulence mechanism of these compounds. Compound 11 inhibited 60% biofilm formation of K. pneumoniae at 70 μg/mL concentration. Compound 5 inhibited the biofilm of K. pneumoniae at 62 μg/mL concentration but also had bactericidal properties at this concentration. Interestingly, compound 2 eradicated the preformed biofilm of both the pathogens at much lower doses as compared to control drug, gentamycin and substrate, enrofloxacin. Cytotoxicity of compounds 2–17 was checked by a standard method using 3T3 normal cell lines (mouse fibroblast), all compounds were found to be noncytotoxic. Conclusion: These compounds can be used alone or with FDA approved drugs to overcome biofilm related K. pneumoniae and S. aureus infections.