Process chemistry

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.

A protocol has been developed that allows the synthesis of 2-aryl/heteroaryl-4-quinolones from readily available, affordable starting materials. The reaction proceeds under microwave conditions with moderate to high yields in the presence of copper catalyst. Short reaction time, good functional group tolerance, high atom economy, non-toxic byproduct and no use of special ligands emphasize the applicability of this method in organic synthesis.

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.

Andrographolide 1, the major constituent of the Indian medicinal plant Andrographis paniculata (Acanthaceae) was converted into the key intermediate 4 by selective oxidative degradation of the C-12,13 olefin bond. The aldehyde functional group present in 4 has been utilized for synthesizing a number of structurally diverse labdane diterpenes. Synthesis and in vitro cytotoxic activity results of the compounds prepared are discussed.

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C–N bonds in good to excellent yields.

Labdane diterpenes are an important class of natural products with a wide variety of biological properties. (À)-Limonidilactone is a labdane diterpene with a novel skeleton isolated from Vitex limonifolia. A new semi-synthetic route from andrographolide, the major constituent of Andrographis paniculata, has been described towards the synthesis of novel labdanes having a limonidilactone type skeleton.

A unified synthetic strategy has been devised for the synthesis of both tedanolide and 13-deoxytedanolide, which involves a cross-metathesis reaction as the key step. We report herein the stereoselective synthesis of the C3-C16 segment (+)-5b and subsequent manipulation of the C12-C13 double bond leading to the preparation of both tedanolides.

Labdane diterpenes are an important class of natural products with a wide variety of biological properties. (−)-Limonidilactone is a labdane diterpene with a novel skeleton isolated from Vitex limonifolia. A new semi-synthetic route from andrographolide, the major constituent of Andrographis paniculata, has been described towards the synthesis of novel labdanes having a limonidilactone type skeleton.A facile synthetic route has been established to convert andrographolide 2 into two novel limonidilactone analogues 3 and 4.

BackgroundWe determined the effect of andrographolide and one of its novel semi-synthetic analog, DRF 3188, on the cell cycle of MCF 7 breast cancer cells.MethodsThe effect of the compounds on cell cycle was determined using FACS and western blot analysis of cell cycle proteins. Hollow fibre assay was used to determine if the compounds had the same effect on the cell cycle in vitro and in vivo.ResultsOur results from the in vitro and in vivo experiments show that both the compounds block the cell cycle at the G0-G1 phase through the induction of the cell cycle inhibitor, p27, and the concomitant decrease in the levels of Cdk4.ConclusionThe results show that the novel semi-synthetic analog, DRF3188, and andrographolide bring about the anti cancer activity by a similar mechanism.

Alterations in the gene encoding for the fibroblast growth factor receptor (FGFR) and upregulation of the vascular endothelial growth factor receptor (VEGFR) are found often in cancer, which correlate with disease progression and unfavorable survival. Additionally, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nM) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nM) with similar potency as it inhibits proliferation in FGFR-dependent cell...

A series of new 4(3H)-quinazolinones were synthesized and evaluated for their cytotoxic activity against a set of human cancer cell lines MDA-MB-231 and MCF-7 (breast), HCT-116 and HT-29 (colon) and A549 (lung). Among the tested compounds, 22a exhibited promising cytotoxic activity against MDA-MB-231 (IC 50 : 3.21 mM) and HT-29 (IC 50 : 7.23 mM) cell lines. The mechanism of action and the apoptosis inducing effect of the compound 22a were studied using the breast cancer cell line MDA-MB-231. Treatment of MDA-MB-231 cell line with compound 22a showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow cytometric analysis indicated that the compound induces G0/G1 phase of cell cycle arrest in a dose dependent manner. The binding modes of the potent compounds with EGFR target protein were investigated by docking studies.

Emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Discovery of new antibacterial agents with new mode of action remains a high priority universally. 4(3H)-quinazolinone, a fused nitrogen heterocyclic compound has emerged as a biologically privileged structure, possessing a wide range of biological properties viz. anticancer, antibacterial, antitubercular, antifungal, anti-HIV, anticonvulsant, antiinflammatory and analgesic activities. Promising antibacterial properties of quinazolinones have enthused the medicinal chemists to explore and develop this fused heterocyclic system for new antibacterial agents. Utilization of quinazolinone core for the design and synthesis of new antibacterial agents has recently gained momentum. This review aims to provide an overview of the structures and antibacterial activity of various 4(3H)-quinazolinone derivatives covering various aspects of in vitro and in vivo pharmacological activities and structure activity relationships (SARs).

Multi-drug resistant Staphylococcus aureus infections have created a critical need for the development of new classes of antibacterials. Discovery of new naturally derived antibacterial agents with new mechanism of action remains a high priority globally. Several of the available antibacterial agents like β-lactams, polyketides, phenylpropanoids, aminoglycosides, macrolides, glycopeptides, streptogramins and lipopeptides are natural products or their semisynthetic variations. In the current scenario of alarming rise in antibacterial resistance, revisiting natural products with modern chemistry and biology tools has fascinated many medicinal chemists for discovery and development of natural products or derived semisynthetic derivatives as effective antibacterial agents. This review underlines the structures and anti-MRSA activity of various natural product derivatives covering recent reports, in vivo activities and brief Structure Activity Relationships (SARs).