Diarylidene-N-Methyl-4-Piperidones and Spirobibenzopyrans as Antioxidant and Anti-Inflammatory Agents.

Curcumin has antioxidant properties resulting from its radical scavenging ability and inhibition of inflammation-associated factors. However, its lack of solubility, instability, and poor bioavailability are impediments to its therapeutic use. As potential alternatives, we synthesized and performed chemical analysis of thirty diarylidene-N-methyl-4-piperidone (DANMP), diheteroarylidene-N-methyl-4-piperidone (DHANMP), and spirobibenzopyran (SBP) derivatives, one of which was also characterized by single crystal X-ray diffraction. All compounds were evaluated for antioxidant activity via 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and for drug-like properties in silico. A subset of five compounds was investigated in terms of aqueous solubilities, which were significantly improved compared to that of curcumin. In vitro assessments of cellular and anti-inflammatory effects were conducted via real time polymerase chain reaction (RT-PCR) and Griess assays to evaluate the presence of inflammatory/activated (M1) markers and production of nitric oxide (NO) species, which are associated with inflammation. The five compounds reduced levels of markers and NO to extents similar to or better than curcumin in inflamed cells, and showed no adverse effects on cell viability. We show that these compounds possess anti-inflammatory properties and may be used as curcumin-substitutes with improved characteristics.

Benzopyrylium salts as new anticancer, antibacterial, and antioxidant agents.

Benzopyrylium salts are an unexplored class of compounds and as a first, this study reports them as potential therapeutic agents. In this effort we pursue the synthesis and in vitro anticancer, antibacterial and antioxidant properties of some novel benzopyrylium salts. The benzopyrylium salts were synthesized and further characterized via UV-vis, IR, 1H-NMR, 13C-NMR and mass spectrometry. The benzopyrylium salts were tested in vitro for anticancer activity across NCI 60 cell line panel. PS-CP-4MO showed the best activity against the MDA-MB-435 cell line of melanoma cancer in terms of the least GI50 (1.78 µM), TGI (3.47 µM) and LC50 (6.77 µM) values and showed selectivity against melanoma, colon cancer and leukemia. Mechanistic studies indicate that this compound inhibits MCF-7 cancer cells by inducing apoptosis and abrogates colony formation and wound healing in the cancer cells. Antibacterial studies show that some of the benzopyrylium salts are active on S. aureus (ATCC 29213) and the best active compound PS-CP-5Cl has a MIC of 8 µg/mL. Antioxidant studies indicate that they have good free radical scavenging properties (PS-CP-5Cl showed activity 1.48 times ascorbic acid). Fulfillment of the Lipinski's parameters of the benzopyrylium salts in silico showed tremendous drug likeness as potential pharmacophore leads.

Synthesis of novel spirobibenzopyrans as potent anticancer leads inducing apoptosis in HeLa cells.

Spirobibenzopyrans are an unexplored class of therapeutics. We report the anticancer activity of novel spirobibenzopyrans, synthesized by a one-pot reaction and extensively characterized. Structure of one of the spirobibenzopyran has been determined by the single crystal XRD technique. The in vitro anticancer activity of these derivatives across the NCI 60-cell line panel was evaluated and for the first time their mechanism of action against HeLa cells was probed via cell morphology analysis and cell cycle analysis. They were determined to be apoptosis inducers with cell cycle arrest in G0/G1 and S phase suggesting CDK-4 protein inhibition and the inhibition of DNA replication. The DNA inhibition was studied and confirmed using the alkaline comet assay for the compound CHX-4MO-SAL showing S phase inhibition. Further, conformity with the in silico Lipinski's score signify the potential of spirobibenzopyrans as anticancer leads.

Synthesis and biological evaluation of new C-12(α/ß)-(N-) sulfamoyl-phenylamino-14-deoxy-andrographolide derivatives as potent anti-cancer agents.

Andrographolide, the major diterpenoidal constituent of Andrographis paniculata (Acanthaceae) and its derivatives have been reported to possess plethora of biological properties including potent anti-cancer activity. In this work, synthesis and in-vitro anti-cancer evaluation of new C-12-substituted aryl amino 14-deoxy-andrographolide derivatives (III a-f) are reported. The substitutions include various sulfonamide moieties -SO2-NH-R1. The new derivatives (III a-e) exhibited improved cytotoxicity (GI50, TGI and LC50) compared to andrographolide (I) and the corresponding 3,14,19-O-triacetyl andrographolide (II) when evaluated against 60 NCI cell line panel. Compounds III c and III e are found to be non-toxic to normal human dermal fibroblasts (NHDF) cells compared to reference drug THZ-1.

Synthesis and in vitro cytotoxicity of novel C-12 substituted-14-deoxy-andrographolide derivatives as potent anti-cancer agents.

Andrographolide, the major labdane diterpenoid from Andrographis paniculata has been reported to be cytotoxic against various cancer cells in vitro. Our research efforts led to the discovery of novel 12-phenyl thio and 12-aryl amino-14-deoxy-andrographolide derivatives (III q and III r) with potent cytotoxic activity, 12-benzyl amino-14-deoxy-andrographolide analogues showing broad range of cytotoxic activity against most of the cell lines and 12-alkyl amino-14-deoxy-andrographolide derivatives being selective to few cell lines (PC-3 and HOP-92), when the selected analogues were evaluated against 60 human cancer cell line panel at National Cancer Institute (N.C.I.), USA. The SAR (structure activity relationship) studies demonstrated potent activity for the compounds containing the following functionalities at C-12: substituted aryl amino/phenyl thio>benzylamine>alkyl amine. The significant cytotoxic activity observed for compounds III q and III r suggest that these could serve as templates for further optimization.

Synthesis of novel pyrazole acetals of andrographolide and isoandrographolide as potent anticancer agents.

Globally, cancer is the most prevalent chronic disease-related cause of death. Although there are many anticancer drugs, some of them have adverse effects. Due to their limited side effects, natural products are preferred over synthetic drugs. Andrographolide and its derivatives are known to be potent anticancer agents. In this context, sixteen novel 3,19-(NH-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide (1a-1h, 2a-2g, 2i) from 3-aryl-1-H-pyrazole-4-carboxaldehydes (a-i) were synthesized. All the synthesized compounds were characterized using 1H NMR, 13C NMR, HRMS, FT-IR, and UV-vis spectroscopy. All the compounds were evaluated against a panel of 60 different human cancer cell lines for their anticancer potential at NCI, USA. Four compounds, having promising GI50s (50% growth inhibitory activity) on all 60-cell lines were selected for further in vitro studies. Out of these four compounds, compound 1g exhibited the best IC50 (3.08 µM) against the colon cancer cell line, HCT-116. Cell cycle analysis, annexin V-FITC/PI, and ROS assays revealed that the apoptosis of HCT-116 cells induced by compound 1g could be mainly attributed to the elevated levels of intracellular ROS. Further, the structure-activity relationship revealed that the pyrazole moiety of andrographolide plays a key role in their anticancer properties. These compounds were further examined for in silico ADMET and Lipinski characteristics to assess their potential as lead compounds.

Antiplasmodial and Antimalarial Activity of 3,5-Diarylidenetetrahydro-2H-pyran-4(3H)-ones via Inhibition of Plasmodium falciparum Pyridoxal Synthase.

A series of 22 different 3,5-diarylidenetetrahydro-2H-pyran-4(3H)-ones (DATPs) were synthesized, characterized, and screened for their in vitro antiplasmodial activities against chloroquine (CQ)-sensitive Pf3D7, CQ-resistant PfINDO, and artemisinin-resistant PfMRA-1240 strains of Plasmodium falciparum. DATP 19 (3,5-bis(4-hydroxy-3,5-dimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) was found to be the most potent (IC50 1.07 µM) against PfMRA-1240, whereas 21 (3,5-bis(3,4,5-trimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) showed IC50 values of 1.72 and 1.44 µM against Pf3D7 and PfINDO, respectively. Resistance indices (RI) as low as 0.2 to 0.5 for 10 (3,5-bis(4-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one) and 20 (3,5-bis(3-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one), and <1 for most other DATPs reveals their greater potency against resistant strains than the sensitive one. The single-crystal XRD data for DATP 21 are reported. In silico support was obtained through docking studies. Killing all three strains within 4-8 h, these DATPs showed rapid kill kinetics toward the trophozoite stage. Furthermore, DATP 18 (3,5-bis(quinolin-4-ylmethylene)tetrahydro-2H-pyran-4(3H)-one) inhibited PfPdx1 enzyme activity with IC50 20.34 µM, which is about twofold lower than that (IC50 43 µM) for an already known inhibitor 4PEHz. At an oral dose of 300 mg/kg body weight, DATPs 19 and 21 were found to be nontoxic to mice, and at 100 mg/kg body weight, DATP 19 was found to suppress parasitaemia, which led to an increase in median survival time by three days relative to untreated control mice in a malaria curative study.

Anti-cancer activity of heteroaromatic acetals of andrographolide and its isomers.

Acetals (2a-d, 3a-d, and 6a-d) of andrographolide (1), 14-deoxy-12-hydroxyandrographolide (4), and isoandrographolide (5) were synthesized using benzaldehyde and heteroaromatic aldehydes. All the synthesized derivatives were characterized using 1H-NMR, 13C-NMR, mass spectrometry, UV, and IR. The compound 6d was characterized via a single-crystal X-ray diffraction study. All the compounds were tested against 60 cell lines of NCI. The acetals (2a-d) of andrographolide (1) exhibited better activity than the acetals (3a-d, and 6a-d) of 12-hydroxyandrographolide (4) and isoandrographolide (5). Preliminary studies suggested that acetals synthesized using benzaldehyde improved anticancer activity. Compound 2a showed the highest growth inhibition of 90.97% against the leukaemia cancer cell line CCRF-CEM. Andrographolide and seven selected compounds were tested against the MDA-MB-231 breast cancer cell line. Compound 3b showed the best activity with an IC50 value of 3 µM among all the tested compounds. Furthermore, this compound 3b was subjected to cell cycle analysis and protein expression confirming apoptosis through the disruption of the mitochondrial potential membrane (Δψ m).

Andrographolide: A natural product template for the generation of structurally and biologically diverse diterpenes.

From times immemorial, natural products have played an important role in the management of human health. Andrographis paniculata, belonging to the family Acanthaceae and its constituents are reported to possess a wide range of biological properties such as anti-cancer, anti-diabetic, anti-inflammatory, anti-bacterial, anti-malarial, anti-hepatitis, anti-HIV, anti-atherosclerosis, hepatoprotective, FXR antagonist, and α-glucosidase inhibition. Andrographolide (1), is identified as the major bioactive constituent of the plant. Promising biological properties of the major constituent Andrographolide (1) along with structural amenability for facile semi-synthetic modifications have led to the generation of structurally diverse bioactive labdane diterpenes by several research groups. The promising biological activities exhibited by these semi-synthetic derivatives have further kindled interest and the continued research is evidenced through publications, patents and could possibly lead to the development of Andrographolide based medicines in future. The present review aims at compiling and discussing various semi-synthetic derivatives of Andrographolide in relation to their biological properties and their mechanisms of action.