Synthesis and SAR study of novel sarsasapogenin derivatives as potent neuroprotective agents and NO production inhibitors

Sarsasapogenin, isolated from rhizomes of Anemarrhena asphodeloides, was found to be able to enhance memory. On the basis of the structure of Sarsasapogenin, a series of derivatives were synthesized and evaluated for their neuroprotective activity in PC12 cells and NO production inhibitory activity in RAW264.7 cell lines. The preliminary structure-activity relationship of them indicated that introduction of carbamate groups at the 3-hydroxyl position of sarsasapogenin might improve neuroprotective activity. Some synthesized derivatives such as AA3, AA4, AA9 and AA13 exhibited both notably neuroprotective activity and NO production inhibitory activity.     

Lead selection of antiparasitic compounds from a focused library of benzenesulfonyl derivatives of heterocycles

A library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive SAR evaluation. Four compounds showed an IC₅₀ between 0.25 and 3 μM against Leishmania donovani and low cytotoxicity. Compound G{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an IC₅₀ similar to the reference drug miltefosine. Seven compounds showed an IC₅₀ below 6 µM against Trypanosoma cruzi, and three of them (E{3}, E{9} and G{3}) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Two promising structures (B{15} and G{15}) showed moderate inhibitory activity against Plasmodium falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with the exception of Trypanosoma brucei rhodesiense), validating the criteria used in the selection of the privileged structures and diversification used to generate this library. SAR analysis showed that the presence of lipophilic and electron withdrawing groups were favorable for the antiparasitic activity.     

Leishmanicidal activity of fungal bioproducts: A systematic review

The genome mining of biosynthetic genes from fungi demonstrates the enormous pharmacological potential that is still little explored. These results have encouraged the scientific community to invest in fungi as a source of innovative alternatives for the treatment of neglected diseases, such as leishmaniasis. Therefore, this work aimed to identify, through a systematic search in the databases of PubMed, Lilacs and Scielo, the existing evidence in the literature regarding the efficacy of the leishmanicidal activity of fungal bioproducts that represent new starting points for the advancement of pharmacotherapy of leishmaniasis. During the search process, 59 articles met all the eligibility criteria and, therefore, were included in this review. The studies demonstrate that different prospecting, cultivation, biotechnological and synthetic modification strategies contribute to the discovery and development of new therapeutic fungal compounds. 39 (66.1%) of the studies presented at least one isolated compound with leishmanicidal activity, while 20 (33.9%) evaluated only crude extracts or semipurified fractions. Terpenes, steroids and quinones were the most prevalent chemical classes among the isolated compounds. There are many studies about active compounds that have been isolated from Penicillium and Aspergillus genera. A large majority (89.8%) of the selected studies been conducted in vitro. Only six studies performed in vivo assay. The species of Leishmania amazonensis and Leishmania donovani were the most evaluated. The results support the hypothesis of the pharmacological potential of fungal bioproducts in the treatment of leishmaniasis.     

Synthesis, growth inhibition, and cell cycle evaluations of novel flavonoid derivatives

As a continuation of our search for potential new anticancer agents, a series of ten flavonoid derivatives has been synthesized by cyclization of substituted chalcones. Target compounds were evaluated for their biological activity. Among them, compounds 1–4 and 9 displayed a significant growth inhibitory action against a panel of tumor cell lines including Jurkat, PC-3, and Colon 205. On treatment with an equitoxic (IC₅₀) concentration, compounds 1–5 and 7–9 blocked cells in the G2/M phase of the Jurkat cell cycle, whereas compound 6 blocked the same in the G0/G1 phase.     

Design,synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1)

The natural product embelin was found to have PAI-1 inhibitory activity with the IC₅₀ value of 4.94 μM. Based on the structure of embelin, a series of analogues were designed, synthesized, and evaluated for their ability to inhibit PAI-1. The SAR study on these compounds disclosed that the inhibitory potency largely depended on the hydroxyl groups at C2 and C5, and the length of the alkyl chains at C3 and C6. Compound 11 displayed the best PAI-1 inhibitory potency with the IC₅₀ value of 0.18 μM.     

Synthesis, cytotoxic activity, and SAR analysis of the derivatives of taxchinin A and brevifoliol

Twenty-one derivatives of taxchinin A (1) and brevifoliol (2) were synthesized and evaluated for cytotoxicity against human non-small lung cancer (A549) cell line. Nine derivatives showed potent activity with IC₅₀ values from 0.48 to 6.22 μM. 5-Oxo-13-TBDMS-taxchinin A (11) and 5-oxo-13,15-epoxy-13-epi-taxchinin A (15) are the most potent derivatives, with IC₅₀ at 0.48 and 0.75 μM, respectively. The structure–activity relationship (SAR) of these compounds established that exocyclic unsaturated ketone at ring C is the key structural element for the activity, while the ,β-unsaturated ketone positioned at ring A has no effect for the activity. The significant cytotoxicity of derivatives 11 and 15 may be due to the conformational change in the taxane rings. The 3D-QSAR study was conducted on this series of compounds, which provided optimal predictive comparative molecular field (CoMFA) model with cross-validated r² (q²) value of 0.64.     

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure–activity relationships will be of interest for future studies on cell proliferation and immune modulation.     

Synthesis and structure activity relationships of schweinfurthin indoles

As part of a program to explore the biological activity of analogues of the natural schweinfurthins, a set of compounds has been prepared where an indole system can be viewed as a substitution for the resorcinol substructure of the schweinfurthin’s D-ring. Twelve of these schweinfurthin indoles have been prepared and evaluated in the 60 cell line screen of the National Cancer Institute. While a range of activity has been observed, it is now clear that schweinfurthin indoles can demonstrate the intriguing pattern of activity associated with the natural stilbenes. In the best cases, these indole analogues display both potency and differential activity across the various cell lines comparable to the best resorcinol analogues.     

Synthesis, alpha 1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin

In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of alpha(1)-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a-3a) for alpha(1)- and alpha(2)-adrenoceptors were evaluated using radioligand ([(3)H]prazosin, [(3)H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a-16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to alpha(1)- and alpha(2)-adrenoceptors. They have shown affinities for alpha(1)-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of alpha(1)-adrenoceptors. Selected compounds (3a-5a, 7a, 13a, 14a) were also evaluated for their alpha(1)-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for alpha(1)-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal alpha(1)-adrenoceptor antagonist.     

Synthesis and SAR study of novel anticancer and antimicrobial naphthoquinone amide derivatives

A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone, menadione and lawsone, with various amino acids were synthesized. The compounds were characterized by ¹H NMR, ¹³C NMR, Mass, IR and elemental analysis. All the compounds were evaluated for their anticancer activity against HeLa and SAS cancer cell lines and 3D-QSAR indicated the presence of electron donating group near sulphur enhanced the activity against HeLa cells. Among the derivatives synthesized, compounds 11f, 10a, 10b and 10g were the most active with IC₅₀ values of 16, 12, 14 and 24.5 μM, respectively. The analogues were also screened for antimicrobial activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas aeruginosa and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). Among the synthesized compounds, 8g, 10g and 11g exhibited maximum antibacterial activity towards MRSA and antifungal activity against FRCA in well diffusion method.     

Antiproliferative and pro-apoptotic activity of novel phenolic derivatives of resveratrol

Gloriosaols A-C, isolated from Yucca gloriosa (Agavaceae), are novel phenolic compounds structurally related to resveratrol. In the present study, we show that gloriosaols possess antiproliferative and pro-apoptotic activity on tumor cells of different histogenetic origin and that their cell growth inhibition potential is higher than that of resveratrol. Despite the close similarities in their structure, gloriosaols A-C exhibited different antiproliferative potency, as the EC(50) ascending order is: gloriosaol C, gloriosaol A, gloriosaol B. Further mechanisms of gloriosaol C cytotoxicity were elucidated in detail in U937 cells, the most sensitive of the cell lines tested. The effect of gloriosaol C on cell growth turned out to be strongly dependent upon the concentration. Gloriosaol C doses lower than the EC(50) value (8 mu-icroM) blocked the cell cycle in G(0)/G(1), with a concurrent decrease in the number of cells in the G(2)/M phases of the cell cycle. At higher doses, this arrest overlaps with the occurrence of apoptosis and necrosis. In the 10-25 microM range of doses, gloriosaol C caused cell death mainly by apoptosis, as measured by hypodiploidia induction, phosphatidyl serine externalization and disruption of mitochondrial transmembrane potential. A switch in the mode of death from apoptosis to necrosis occurred at doses of gloriosaol C higher than 30 microM. Gloriosaol C was found to induce production of reactive species dose-dependently, but also to counteract their elevation in stressed cells. Thus, the different fate of cells, that is cell cycle arrest or cell death, in response to different doses of gloriosaol C might be related to the extent of induced oxidative stress.     

A synthetic approach to novel carvotacetone and antheminone analogues with anti-tumour activity

A synthetic approach to analogues of the terpenoid natural product antheminone A is described which employs (?)-quinic acid as starting material. A key conjugate addition step proved to be unpredictable regarding its stereochemical outcome however the route allowed access to two diastereoisomeric series of compounds. The results of biological assay of the toxicity of the target compounds towards non-small-cell lung cancer cell line A549 are reported.     

Anti-inflammatory activity of benzophenone and xanthone derivatives isolated from Garcinia (Clusiaceae) species

Species of the genus Garcinia have been the source of many benzophenone and xanthone derivatives. Recent data regarding potent biological properties of natural compounds in Garcinia species led us to investigate the in vitro anti-inflammatory effect of three known xanthones, lichexanthone (1), 1,3,6,7-tetrahydroxyxanthone (2), 1,3,5,6-tetrahydroxyxanthone (3), two new xanthones 1-hydroxy-3,6,7-tri-O,O,O-triprenylxanthone (4), 1,6-dihydroxy-3,7-di-O,O-diprenylxanthone (5) and two benzophenones isoxanthochymol (6), guttiferone E (7), isolated from Garcinia nobilis and Garcinia punctata. The Griess assay was used for the measurement of nitric oxide (NO) production in RAW264.7 macrophages and the ferrous oxidation-xylenol orange assay was used to determine the 15-lipoxygenase (15-LOX) inhibitory activity. All the compounds had inhibitory effect on 15-LOX activity to different extents. Compound (7) had the highest anti-LOX activity with an IC₅₀ value of 43.05 μg/mL. At the highest studied concentration (25 μg/mL), compound (4) had the most potent inhibitory activity against NO release with a% of inhibition of 95.42% and less cytotoxic effect on RAW264.7 cells (% of cell viability of 81.40).The results presented here suggest that 1,3,5,6-tetrahydroxyxanthone (3) and guttiferone E (7) are promising inhibitors of NO production and 15-LOX activity. Further studies should be considered in order to elucidate the mechanism by which these compounds exert their inhibitory activities.     

Discovery of imidazopyridine derivatives as novel c-Met kinase inhibitors: Synthesis,SAR study,and biological activity

Receptor tyrosine kinase c-Met acts as an alternative angiogenic pathway in the process and contents of cancers. A series of imidazopyridine derivatives were designed and synthesized according to the established docking studies as possible c-Met inhibitors. Most of these imidazopyridine derivatives displayed nanomolar potency against c-Met in both biochemical enzymatic screens and cellular pharmacology studies. Especially, compound 7 g exhibited the most inhibitory activity against c-Met with IC₅₀ of 53.4 nM and 253 nM in enzymatic and cellular level, respectively. Following that, the compound 7 g was docked into the protein of c-Met and the structure-activity relationship was analyzed in detail. These findings indicated that the novel imidazopyridine derivative compound 7 g was a potential c-Met inhibitor deserving further investigation for cancer treatment.     

Design,synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC₅₀ value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC₅₀ value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.     

Discovery and SAR study of hydroxyacetophenone derivatives as potent,non-steroidal farnesoid X receptor (FXR) antagonists

Compound 1 (IC₅₀ = 35.2 ± 7.2 μM), a moderate FXR antagonist was discovered via high-throughput screening. Structure–activity relationship studies indicated that the shape and the lipophilicity of the substituents of the aromatic ring affect the activity dramatically, increasing the shape and the lipophilicity of the substituents of the aromatic ring enhances the potency of FXR antagonists. Especially, when the OH at C2 position of the aromatic ring was replaced by the OBn substituent (analog 2b), its activity could be improved to IC₅₀ = 1.1 ± 0.1 μM. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity.     

Synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition

The synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition and significantly improved MIC against Candida parapsilosis and echinocandin resistant-Candida is described.     

Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1–25), characterized through different spectroscopic techniques such as ¹HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC₅₀ value ranging between 1.078 ± 0.19 and 2.926 ± 0.05 µM when compared with acarbose having IC₅₀ = 0.62 ± 0.22 µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC₅₀ values 1.644 ± 0.128, 1.078 ± 0.19, 1.245 ± 0.25, 1.843 ± 0.19, 1.350 ± 0.24, 1.629 ± 0.015, 1.353 ± 0.232, 1.359 ± 0.119 and 1.488 ± 0.07 µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies.     

Synthesis and anti-tumor activity of glycosyl oxadiazoles derivatives

A new series of glycosyl oxadiazoles compounds were synthesized and characterized through ¹H NMR, ¹³C NMR, IR and HRMS. The anti-tumor activities for MDA-MB-231 of all these new compounds were screened in vitro by MTT assay. Due to the modification of gastrodin analogues, the anti-tumor activities of these 1,3,4-oxadiazoles derivatives were greatly improved. Six compounds (6c, 6d, 6i, 6j, 6k and 6l) displayed relatively higher MDA-MB-231 potency with IC₅₀ values (0.89, 0.26, 1.35, 3.60, 0.95 and 1.08 μM) compared with the reference medicine Rosiglitazone (5.23 μM).