Suresh Mandava

Moracin M inhibits airway inflammation by interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo.

The therapeutic effectiveness of moracins as 2-arylbenzofuran derivatives against airway inflammation was examined. Moracin M, O, and R were isolated from the root barks of Morus alba, and they inhibited interleukin (IL)-6 production from IL-1β-treated lung epithelial cells (A549) at 101-00μM. Among them, moracin M showed the strongest inhibitory effect (IC50=8.1μM). Downregulation of IL-6 expression by moracin M was mediated by interrupting the c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moracin derivatives inhibited inducible nitric oxide synthase (iNOS)-catalyzed NO production from lipopolysaccharide (LPS)-treated alveolar macrophages (MH-S) at 50-100μM. In particular, moracin M inhibited NO production by downregulating iNOS. When orally administered, moracin M (20-60mg/kg) showed comparable inhibitory action with dexamethasone (30mg/kg) against LPS-induced lung inflammation, acute lung injury, in mice with that of dexamethasone (30mg/kg). The action mechanism included interfering with the activation of nuclear transcription factor-κB in inflamed lungs. Therefore, it is concluded that moracin M inhibited airway inflammation in vitro and in vivo, and it has therapeutic potential for treating lung inflammatory disorders.

Identification and structural elucidation of three new tadalafil analogues found in a dietary supplement

Compounds elucidated as new tadalafil analogues were found to be adulterated in a dietary supplement and detected during routine analysis by HPLC with photodiode array detection. The UV spectra of these compounds were found to be almost identical to that of tadalafil. The unknown compounds were isolated by preparative HPLC and elucidated by quadrupole-time-of-flight MS and NMR spectroscopy. Two compounds were identified as cyclopentyltadalafil and trans-cyclopentyltadalafil, from the substitution of the tadalafil N-methyl group with a cyclopentyl group. Another analogue was a dimeric form of tadalafil with an N-cyclopentyl group. This represents the first report of the elucidation of compounds used as adulterants in a dietary supplement.

Identification of a new tadalafil analogue in an adulterated dietary supplement: trans-Bisprehomotadalafil.

A new tadalafil analogue was identified along with homotadalafil during routine screening of an adulterated dietary supplement using HPLC-DAD. The UV spectrum of this analogue was almost identical with that of tadalafil. This compound was isolated from the supplement by using semi-preparative HPLC and its structure was subsequently elucidated by performing Q-TOF/MS/MS and NMR spectroscopic experiments. The spectral data indicate that this tadalafil analogue is a dimeric compound that consists of an ethylamino group and two pretadalafil moieties. NOE experiments and comparison with (1)H NMR spectra of tadalafil and trans-tadalafil suggested the trans-relationship between the substituents on piperidine rings in the pretadalafil moieties.

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.

Collision-induced dissociation pathways of H 1 -antihistamines by electrospray ionization quadrupole time-of-flight mass spectrometry

Over the past decades, mass spectrometry technologies have been developed to obtain mass accuracies of one ppm or less. Of the newly developed technologies, quadrupole time-of–flight mass spectrometry (Q-TOF–MS) has emerged as being well suited to routine and high-throughput analyses of pharmaceuticals. Dietary supplements and functional foods have frequently been found to be contaminated with pharmaceuticals. In our continuous efforts to develop methodologies to protect public health against adulterated dietary supplements, we have constructed a mass spectral database for 21 H1-antihistamines encountered as adulterants by using liquid chromatography-electrospray ionization (LC-ESI)/Q-TOF–MS, and have proposed their possible collision-induced dissociation pathways. This database will be very useful for the rapid and accurate detection of H1-antihistamines (known) and their analogues (unknown) illegally added to dietary supplements as well as in other sample matrices.

Novel metabolites from Trichoderma atroviride against human prostate cancer cells and their inhibitory effect on Helicobacter pylori and Shigella toxin producing Escherichia coli

The present study aimed to purify and identify the metabolites from T. atroviride using high-performance liquid chromatography (HPLC) and 1H and 13C nuclear magnetic resonance spectrometer (NMR) followed by analyzing their toxicological, antibacterial and anticancer properties. This work identified two metabolites - TM1 and TM2. TM1 was in two forms: (i) 1, 3-dione-5, 5-dimethylcyclohexane; and, (ii) 2-enone-3hydroxy -5,5-dimethylcylohex, while TM2 was 4H-1,3-dioxin-4-one-2,3,6-trimethyl. These metabolites did not exhibit any irritant or allergic reaction as revealed by HET- CAM test. TM2 significantly inhibited the growth of H. pylori and Shigella toxin producing Escherichia coli (STEC) as evident by in vitro and microscopic observations of bacterial cell death. TM2 also induced the cell death and cytotoxicity, as revealed by cell viability test and western blot analysis. According to microscopic, flow cytometer and western blot analysis, TM2 treated cells displayed higher ROS, cell death, and apoptosis-related protein expression than TM1 and control. This study concluded that TM2 derived from T. atroviride was a potential therapeutic agent for anti-prostate cancer and antibiotic agent against MDR- H. pylori and STEC and it is also recommended to carry out further in vivo animal model experiments with improved stability of the metabolites for future pharmaceutical trails.

Isolation and characterisation of a novel sildenafil analogue adulterant, desmethylpiperazinyl propoxysildenafil, in a dietary supplement

A new sildenafil analogue was detected during routine screening of dietary supplements suspected to be adulterated with an erectile dysfunction drug(s) using HPLC-DAD. The UV spectrum of this compound was highly similar to that of sildenafil and almost identical to that of desmethylpiperazinyl sildenafil. The analogue was purified by using semi-preparative HPLC and structurally elucidated by performing mass spectrometric and NMR spectroscopic experiments. The spectral data revealed that this sildenafil analogue bears an n-propoxy group instead of an ethoxy group and possesses no methylpiperazinyl moiety. The isolated compound, structure of which was further confirmed by spectral comparison with synthetic one, was thus named as desmethylpiperazinyl propoxysildenafil.

Preservative effect of Chinese cabbage (Brassica rapa subsp. pekinensis) extract on their molecular docking, antioxidant and antimicrobial properties

This study aimed at investigating the antimicrobial activity of different solvent extracts of Chinese cabbage Brassica rapa subsp. pekinensis (BRARP) and their antioxidant and cytotoxicity properties. Of the different solvents extracts, the chloroform extracts (CE) were significantly inhibited the bacterial pathogens at minimum inhibitory concentration (MIC) of 16.5 mg.mL-1. Biochemical analysis revealed that total phenol (62.6 ± 0.05 mg GAE.g-1) and flavonoids (27.6 ± 0.04 mg QE.g-1) were higher in the extracts of BRARP, which resulted in enhanced antioxidant activity in CE. A total of eight dominant compounds were detected in the potent antimicrobial extract from BRARP based on GC-MS analysis. The molecular interactions study revealed that, among the screened compounds the 1,2-benzenedicarboxylic acid and 2,3-dicyanopropionamide interacted with the active site of pathogenicity and survival related protein with lipopolysaccharide (LpxC) with higer binding energy. This work concluded that the 1, 2-Benzenedicarboxylic acid and 2, 3-Dicyanopropionamide from BRARP was reported to be good non-cytotoxic and antioxidant antimicrobials against bacterial pathogens.

Stereoselective Protection-Free Asymmetric Total Synthesis of (+)-Chamuvarinin, a Potent Anticancer and Antitrypanosomal Agent: Substrate-Controlled Construction of the Adjacently Linked Oxatricyclic Core by Internal Alkylation

A stereoselective protection-free asymmetric total synthesis of (+)-chamuvarinin (1), a potent anticancer and antitrypanosomal agent, has been accomplished. The adjacently linked [bis(tetrahydrofuran)]tetrahydropyran (THF-THF-THP) core of this natural product with seven stereogenic centers was constructed in a completely substrate-controlled fashion. The inter-ring stereochemistry ( threo,threo,threo) of the oxatricyclic core was established in a stereoselective fashion by a chelation-controlled Keck allylation, whereas the intraring cis or trans relative stereochemistry was controlled by a stereoselective internal alkylation.

Identification and characterization of an indazole-3-carboxamide class synthetic cannabinoid: 2-[1-(cyclohexylmethyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoic acid (DMBA-CHMINACA)

Illicit psychoactive substances have threatened public health worldwide. An active metabolite of ADB-CHMINACA and MDMB-CHMINACA was identified for the first time in a powder-type product found in an airmail package. The structure of compound 1 was elucidated by a combination of gas chromatography-mass spectrometry (GC-MS), liquid chromatography-high resolution mass spectrometry (LC-HRMS), infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. Compound 1 was proven to be an analogue of MDMB-CHMINACA, an indazole-based synthetic cannabinoid. The methyl ester group in MDMB-CHMINACA was replaced with a carboxylic acid group in compound 1. Compound 1 was determined as 2-[1-(cyclohexylmethyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoic acid and named as DMBA-CHMINACA.