Discovery of novel dihydronaphthalene-imidazole ligands as potential inhibitors of Staphylococcus aureus multidrug resistant NorA efflux pump: A combination of experimental and in silico molecular docking studies.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

Aconitum heterophyllum Wall. ex Royle: A critically endangered medicinal herb with rich potential for use in medicine.

Aconitum heterophyllum (Patrees) is a critically endangered medicinal herb of the northwestern Himalayas and has enormous pharmacological potential. It is the only nonpoisonous member of the genus Aconitum, and has been used as a medicinal herb since ancient times. A. heterophyllum is an important ingredient in many traditional systems of medicine. Mostly, it is harvested for its roots, and its medicinal properties are due to the presence of diverse bioactive secondary metabolites, commonly known as aconites. Our understanding of the pharmacological properties of this intriguing genus is continuously growing due to its broad chemical diversity. The therapeutic uses identified by traditional medicinal practice are receiving extensive study. Multiple in vitro experimental investigations of A. heterophyllum have reported the analgesic, anti-inflammatory, antiarrhythmic, antiparasitic and anticancer properties, as well as its effects on the central nervous system. In this review, we highlight the classification, distribution, commerce, traditional uses, phytochemistry, pharmacology and conservation measures relevant to this species. Additionally, this review includes the biosynthetic pathways of A. heterophyllum's key constituents, which could be targeted to enhance the expression levels of desired metabolites via genetic interventions. Studying the genomics, transcriptomics, proteomics and metabolomic aspects of this species would be helpful in developing highly designed genotypes and chemotypes of this species to be used in commercial production.

Photooxidation Coupled Kabachnik-Fields and Bigenelli reactions for Direct Conversion of Benzyl alcohols to α-Amino Phosphonates and Dihydropyrimidones.

A tandem one-pot solvent free approach for the direct conversion of benzyl alcohols to α-amino phosphonates and dihydropyrimidones is reported. The method relies on a metal free photo-oxidation of benzyl alcohols to benzaldehydes under UV irradiation using ammonium perchlorate followed by Kabachnik-Fields and Biginelli reactions. The reaction conditions are moderate and metal free with good substrate scope. The control experiments were performed to investigate the role of the ammonium perchlorate and molecular oxygen as oxidants. The quenching experiments in the presence of TEMPO and other radical quenchers suggest radical based mechanism.

A convergent synthesis of novel alkyne-azide cycloaddition congeners of betulinic acid as potent cytotoxic agent.

In an endeavour to develop potent anti-tumor agents from betulinic acid (BA), a series of C-28 derived 1,2,3-triazolyl derivatives were designed and synthesized by employing Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. All the derivatives were evaluated for cytotoxic activity by MTT assay against five different human cancer cell lines: lung (A549), colon (HCT116), prostate (PC3), pancreatic (MIA PaCa-2) and breast (T47D). The data revealed that compounds 11c, 11d, 11g, 11h and 13a possess most promising cytotoxic potential. The compound 11h was one of the most active compounds, with IC50 values in the range of 4-6µM against all the five cancer cell lines. The results of this study suggested that derivatives with free -OH (11c, 11d and 11g) and free -COOH (11h and 13a) substitutions in the triazole moiety introduced at the C-28 position significantly improved the anti-tumor activity and may be the favourable position to synthesize potent anticancer leads from BA. Introduction of a non polar alkyl groups at C-28 position (10, 12 and 14) resulted in the significant loss of the activity. Further, DAPI staining, ROS generation and wound healing experiments revealed that compound 11h induces apoptosis in HCT-116 cells.

T- and B-cell immunosuppressive activity of novel α-santonin analogs with humoral and cellular immune response in Balb/c mice.

In continuation of our endeavours to synthesize immunosuppressive agents from α-santonin, we report herein the design and synthesis of a new series of α-santonin derived O-aryl/aliphatic ether, ester and amide analogs and the evaluation of their immunosuppressive activities. The in vitro studies led to several analogs with significant immunosuppressive effects by inhibiting ConA and LPS stimulated T- and B-cell proliferation in a dose dependent manner. The more significant compounds 4d, 4e, 4f, 4h, 6a and 6b displayed potent inhibitory activity on the mitogen-induced T- and B-cell proliferation in comparison to α-santonin 1. Compound 4e displayed stupendous in vitro immunosuppressive effects with ∼80% suppression of B and ∼75% suppression of T lymphocyte proliferation, respectively. The in vivo investigation on BALB/c mice revealed that non-cytotoxic compound 4e suppresses both humoral and cellular immunity.

Biologically active xanthones from Codonopsis ovata.

Five new xanthones, named coxanthones A-E (1-5), together with 21 known secondary metabolites (6-26) that include seven xanthones, five flavonoids, two steroids and seven triterpenoids were isolated from the chemically unexplored whole plant Codonopsis ovata. The structures of new metabolites were elucidated by HRMS, interpretation of NMR spectra and other spectroscopic techniques. The absolute configuration of the stereogenic centre of coxanthone B (2) was determined by electronic circular dichroism (ECD) spectroscopy. This is the first report of xanthones from the genus Codonopsis. All isolated metabolites were evaluated for cytotoxic activity by SRB assay against six human cancer cell lines A549 (lung), PC-3 (prostate), HCT-116 (colon), MCF-7 (breast), SF-295 (CNS), and MDAMB-435 (melanoma). Among the new compounds, coxanthone B (2) exhibited significant inhibitory activity against SF-295 and MDAMB-435 with IC50 values of 7.0 and 15.0 µM, respectively. Coxanthone A (1) displayed cytotoxicity against A549 cell line at IC50 value of 22.5 µM. Cytotoxic activity of 1-hydroxy-3,5-dimethoxyxanthone (7), swertiperenine (9) and 1,7,8-trihydroxy-3-methoxyxanthone (10) are reported here first time that exhibited the IC50 values of 3.0, 5.0 and 21.0 µM against A549, MDAMB-435, and A549 cell lines, respectively. Kaempferol (13) showed most potent cytotoxic activity with an IC50 values in the 1.0-2.3 µM range against all tested cancer cell lines.

Synthesis of α-santonin derived acetyl santonous acid triazole derivatives and their bioevaluation for T and B-cell proliferation.

A new series of α-santonin derived acetyl santonous acid 1,2,3-triazole derivatives were synthesised using Huisgen 1,3-dipolar cyclo-addition reaction (click chemistry approach) and evaluated for their in vitro inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among the synthesised series, compounds 2-10 and 19 exhibited significant inhibition against ConA and LPS stimulated T-cell and B-cell proliferation in a dose dependent manner. More significantly compounds 4, 9-10 and 19 exhibited potent inhibition activity with remarkably lower cytotoxicity on the mitogen-induced T cell and B cell proliferation at 1 µM concentration. The compound 6 displayed potent immunosuppressive effects with ∼89% against LPS induced B-cell and ∼83% against ConA stimulated T-cell proliferation at 100 µM concentration without cytotoxicity. Compound 10 was more selective against B cell proliferation and exhibited 81% and 69% suppression at 100 and 1 µM concentration respectively. The present study led to the identification of several santonin analogs with reduced cytotoxicity and strong inhibition activity against the cell proliferation induced by the mitogens.

Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents.

Cytotoxic agents from nature are presently the mainstay of anticancer chemotherapy, and the need to reinforce the arsenal of anticancer agents is highly desired. Chemical transformation studies carried out on betulinic acid, through concise 1,2,3-triazole synthesis via click chemistry approach at C-3position in ring A have been evaluated for their cytotoxic potentiation against nine human cancer cell lines. Most of the derivatives have shown higher cytotoxic profiles than the parent molecule. Two compounds i.e. 3{1N(2-cyanophenyl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid (7) and 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid (13) displayed impressive IC50 values (2.5 and 3.5 µM respectively) against leukemia cell line HL-60 (5-7-fold higher potency than betulinic acid). As evident from various biological end points, inhibition of cell migration and colony formation, mitochondrial membrane disruption followed by DNA fragmentation and apoptosis, is demonstrated.