Gallic Acid Derived 1, 2-Diarylindole as a Potential Antifungal Agent against Candida Strain.

BACKGROUND: In recent decades, Candida albicans has become a serious issue for public health. The worldwide rapid rise in drug resistance to conventional therapies is the main contributing reason. Moreover, because of their potent activity at low concentrations and apparent lack of toxicity, compounds originating from plants are used in therapeutic treatments because of their potent activity at low concentrations and apparent lack of toxicity. Particularly in immunocompromised people, Candida species can result in a wide range of ailments. OBJECTIVES: Present manuscript describes antifungal activity of an indole derivative 1-(4-((5- methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1- amine (7, 100DL-6) by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS- Delhi). METHODS: The synthetic strategy for the preparation of indole derivatives was modified through Fischer indole reaction. Antifungal activity of an indole derivative 1-(4-((5-methoxy-2-(3,4,5- trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1-amine (7, 100DL-6) was done by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS-Delhi). Compound 100DL-6 efficacy was determined by Combination synergy study, ergosterol binding assay, MTT toxicity study and Mutagenicity. RESULTS: Compound 100DL-6 was obtained in 65% yield on desired motifs. Docking scores found were 100DL-6 (-8.7 kcal/mol) and Fluconazole (-7.6 kcal/mol). Further, RMSD were shown for 100DL6 (0.26 ± 0.23 nm) and fluconazole (1.2 ± 0.62 nm). Indole derivative 100DL-6 was active against the tested fungal pathogens and the total zone of inhibition was measured between 13-14 mm in diameter and MIC values between 31.25 µg/mL to 250 µg/mL and MFC values between 62.5 µg/mL to 500 µg/mL. In checkerboard assay synergistic mode of interaction of 100DL-6 with known antifungal drugs was observed. In the presence of ergosterol 100DL-6 and standard drug (s) increased their MIC values, demonstrating a considerable affinity for ergosterol. Compound 100DL-6 was considered to be less-cytotoxic to the cells as determined by MTT assay. Lead compound 100DL-6 was found to be non-mutagenic. CONCLUSION: In the present study, 100DL6 (indole derivatives) significantly abrupted the ergosterol biosynthetic pathway and showed moderate anti-candidal effects. These studies suggest that 100DL6 significantly enhances antifungal effect of clinical drug fluconazole synergistically and may be considered as in clinical trial prior to some extensive in-vivo validations.

Synergistic Antibacterial Activity of Gallic Acid Based Chalcone Indl 2 by Inhibiting Efflux Pump Transporters.

As a part of novel discovery of drugs from natural resources, present study was undertaken to explore the antibacterial potential of chalcone Indl-2 in combination with different group of antibiotics. MIC of antibiotics was reduced up to eight folds against the different cultures of E. coli by both chalcones. Among the two compounds, the i. e. 1-(3', 4,'5'-trimethoxyphenyl)-3-(3-Indyl)-prop-2-enone (6, Indl-2), a chalcone derivative of gallic acid (Indl-2) was better along with tetracycline (TET) worked synergistically and was found to inhibit efflux transporters as obvious by ethidium bromide efflux confirmed by ATPase assays and docking studies. In combination, Indl-2 kills the MDREC-KG4 cells, post-antibiotic effect (PAE) of TET was prolonged and mutant prevention concentration (MPC) of TET was also decreased. In-vivo studies revealed that Indl-2 reduces the concentration of TNF-α. In acute oral toxicity study, Indl-2 was non-toxic and well tolerated up-to dose of 2000 mg/kg. Perhaps, the study is going to report gallic acid derived chalcone as synergistic agent acting via inhibiting the primary efflux pumps.

Rapid metabolic fingerprinting with the aid of chemometric models to identify authenticity of natural medicines: Turmeric, Ocimum, and Withania somnifera study.

Herbal medicines are popular natural medicines that have been used for decades. The use of alternative medicines continues to expand rapidly across the world. The World Health Organization suggests that quality assessment of natural medicines is essential for any therapeutic or health care applications, as their therapeutic potential varies between different geographic origins, plant species, and varieties. Classification of herbal medicines based on a limited number of secondary metabolites is not an ideal approach. Their quality should be considered based on a complete metabolic profile, as their pharmacological activity is not due to a few specific secondary metabolites but rather a larger group of bioactive compounds. A holistic and integrative approach using rapid and nondestructive analytical strategies for the screening of herbal medicines is required for robust characterization. In this study, a rapid and effective quality assessment system for geographical traceability, species, and variety-specific authenticity of the widely used natural medicines turmeric, Ocimum, and Withania somnifera was investigated using Fourier transform near-infrared (FT-NIR) spectroscopy-based metabolic fingerprinting. Four different geographical origins of turmeric, five different Ocimum species, and three different varieties of roots and leaves of Withania somnifera were studied with the aid of machine learning approaches. Extremely good discrimination (R2 > 0.98, Q2 > 0.97, and accuracy = 1.0) with sensitivity and specificity of 100% was achieved using this metabolic fingerprinting strategy. Our study demonstrated that FT-NIR-based rapid metabolic fingerprinting can be used as a robust analytical method to authenticate several important medicinal herbs.

Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Anti-inflammatory, anti-oxidant and cardio-protective properties of novel fluorophenyl benzimidazole in L-NAME-induced hypertensive rats.

BACKGROUND: Chronic inflammation and oxidative stress play important role in development of hypertension. Recently, we have reported novel fluorophenyl benzimidazole (FPD) for vasorelaxation and antihypertensive activity in SHRs. The present study envisaged the anti-inflammatory, anti-oxidant and cardio-protective properties of FPD in L-NAME model of hypertension with special emphasis on reversal of vascular remodeling, gene expression and restoration of hemodynamic. METHODS: Antihypertensive activity of FPD was evaluated in L-NAME treated Wistar rats, and the parameters studied were anti-inflammatory activity, histomorphological changes, gene expression profile and anti-oxidant properties. RESULTS: FPD at 50 and 100 mg kg-1 once daily for 15 days significantly reduced SBP, DBP and MAP in L-NAME treated rats and the values were well comparable to vehicle control group. Further, FPD treatment showed a significant increase in hepatic GSH content, SOD, catalase activity, decreased MDA level and restoration of pro and anti-inflammatory cytokine levels. The mRNA expression profile of genes associated with regulation of vascular tone, remodeling and inflammation showed a significant level of alteration by chronic L-NAME treatment and was dose-dependently restored upon treatment with FPD. Further, FPD treatment restored serum lipid profile, CK, CK-MB and LDH level and also reversed the histomorphological changes like intimal wall thickening, hyperplasia of cardiomyocytes and ventricular wall thickening. CONCLUSIONS: Taken together, FPD produced potent antihypertensive activity in L-NAME model through vasorelaxation, anti-oxidative and anti-inflammatory properties leading to restoration of serum lipid profile, cardiac biomarker, expression profile of target genes and reversal of histomorphological changes.

Synthesis, Molecular Docking, and 2D-QSAR Modeling of Quinoxaline Derivatives as Potent Anticancer Agents against Triple-negative Breast Cancer.

BACKGROUND: Breast carcinomas aka triple-negative breast cancers (TNBC) are one of the most complex and aggressive forms of cancers in females. Recently, studies have shown that these carcinomas are resistant to hormone-targeted therapies, which makes it a priority to search for effective and potential anticancer drugs. The present study aimed to synthesize and develop the 2Dquantitative structural activity relationship model (QSAR) of quinoxaline derivatives as a potential anticancer agent. METHODS: Quinoxaline derivatives were designed and synthesized (8a-8i and 9a-9d) and the 2DQSAR model against TNBC was developed using VLife MDS v4.4. The anticancer activity was investigated against the TNBC MDA-MB-231 cell line using an MTT cytotoxicity assay. Molecular docking studies along with the estimation of ADMET parameters were done using Discovery Studio. The most potent compound was docked against the ß-tubulin protein target (PDB: 4O2B), using the Autodock Vina v0.8 program. RESULTS: Eleven derivatives of quinoxaline were designed and synthesized (8a-8i and 9a-9d) and a 2D-QSAR model was developed against the TNBC MDA-MB231 cell line. The regression coefficient values for the training set were (r2) 0.78 and (q2) 0.71. Further, external test set regression (pred_r2) was 0.68. Five molecular descriptors viz., energy dispersive (Epsilon3), protein-coding gene (T_T_C_6), molecular force field (MMFF_6), most hydrophobic hydrophilic distance (XA), and Zcomp Dipole were identified. After ADMET, the best analog 8a showed the best activity against the TNBC cell line. The best-predicted hit '8a' was found to bind within the active site of the ß- tubulin protein target. CONCLUSION: The newly synthesized quinoxaline compounds could serve as potent leads for the development of novel anti-cancer agents against TNBC.

2-Benzyllawsone protects against polymicrobial sepsis and vascular hyporeactivity in swiss albino mice.

BACKGROUND: Novel naphthoquinone, 2-benzyllawsone (LT-9) was evaluated against vascular hyporeactivity and sepsis in cecal ligation and puncture (CLP) model in mice in view of its preliminary antibacterial and anti-inflammatory properties and to explore whether pretreatment with the molecule could restore vascular tone and contractile response to norepinephrine. METHODS: Evaluation of LT-9 against vascular hyporeactivity, hypotension, and sepsis-related inflammation and infection was carried out in the CLP model in Swiss albino mice and aortic smooth muscle cells in vitro. RESULTS: LT-9 showed potent reversal of the vascular hyporeactivity in CLP mice aorta. The increased contraction response to norepinephrine in CLP mouse aorta by LT-9 was mediated by opening of L-type voltage-dependent calcium channels (VDCC) verified by ex vivo experiment where LT-9 enhanced contraction response to CaCl2 in the aorta while abolishing the contraction response of known VDCC opener Bay K8644. LT-9 in aortic smooth muscle cells showed Fluo-4 mediated increase in calcium fluorescence. Oral administration of LT-9 at 50 and 100 mg kg-1 day-1 for 15 days significantly enhanced the mean survival time, improved hemodynamic and Electrocardiogram (ECG) profile, and aortic tissue reactivity in CLP mice. Further, LT-9 significantly reversed the perturbation of the expression profile of inflammatory cytokines, reduced the splenic microbial load, and was well tolerated in oral toxicity. CONCLUSIONS: LT-9 showed potent biological activity against sepsis and was found to be well tolerated in the toxicity study in Swiss albino mice and showed promise for the benzyllawsone class of molecules against sepsis for the development of novel pharmacophore.

Plant isoquinoline alkaloids: Advances in the chemistry and biology of berberine.

Alkaloids are one of the most important classes of plant bioactives. Among these isoquinoline alkaloids possess varied structures and exhibit numerous biological activities. Basically these are biosynthetically produced via phenylpropanoid pathway. However, occasionally some mixed pathways may also occur to provide structural divergence. Among the various biological activities anticancer, antidiabetic, antiinflammatory, and antimicrobial are important. A few notable bioactive isoquinoline alkaloids are antidiabetic berberine, anti-tussive codeine, analgesic morphine, and muscle relaxant papaverine etc. Berberine is one of the most discussed bioactives from this class possessing broad-spectrum pharmacological activities. Present review aims at recent updates of isoquinoline alkaloids with major emphasis on berberine, its detailed chemistry, important biological activities, structure activity relationship and implementation in future research.

Microtubule associated proteins as targets for anticancer drug development.

The dynamic equilibrium of tubulin-microtubule is an essential aspect of cell survivality. Modulation of this dynamics has become an important target for the cancer drug development. Tubulin exists in the alpha-beta dimer form which polymerizes to form microtubule and further depolymerizes back to tubulin dimer. The microtubule plays an essential role in mitosis and cell multiplication. Antitubulin drugs disturb the microtubule dynamics which is essentially required for DNA segregation and cell division during mitosis so killing the cancerous cells. Microtubule Associated Proteins (MAPs) interact with cellular cytoskeletal microtubules. MAPs bind to the either polymerized or depolymerized tubulin dimers within the cell and mostly causing stabilization of microtubules. Some of the tubulin binding drugs are in clinical use and others in clinical trial. MAPs inhibitors are also in clinical trial. Post-translational modification of lysine-40 either in histone or in alpha tubulin has an important role in gene expression and is balanced between histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDAC inhibitors have the anticancer properties to form a drug for the treatment of cancer. They act by inducing cell cycle arrest and cell death. Some of the HDAC inhibitors are approved to be used as anticancer drug while others are under different phases of clinical trial. The present review updates on various MAPs, their role in cancer progression, MAPs inhibitors and their future prospects.

Antihypertensive Effect of a Novel Angiotensin II Receptor Blocker Fluorophenyl Benzimidazole: Contribution of cGMP, Voltage-dependent Calcium Channels, and BKCa Channels to Vasorelaxant Mechanisms.

Background: The current study presents the novel angiotensin II receptor blocker fluorophenyl benzimidazole (FPD) as an antihypertensive agent in the SHR model of hypertension. We investigated the role of cGMP, voltage-dependent L-type calcium channels, and BKCa channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. Methods: The antihypertensive effect of FPD was examined using an invasive technique measuring blood pressure in SHR animals. Using a myograph, tension measurement was completed in the superior mesenteric artery to elucidate the mechanisms of vasorelaxation involving AT1 receptors, the NO/cGMP pathway, L-type calcium channels, and BKCa channels. Ion flux (Ca2+, K+) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by in silico docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. Results: FPD significantly decreased blood pressure in SHR. It relaxed superior mesenteric arteries in a concentration-dependent manner and significantly inhibited angiotensin II-induced contraction. The relaxation response was also mediated by an increase in tissue cGMP levels, inhibition of L-type calcium channels, and the opening of BKCa channels. FPD further enhanced efflux of K+ and inhibited Bay K8644-stimulated Ca2+ influx in aortic smooth muscle cells and docked well in an in silico study with the targets. It was well tolerated in the toxicity study. Conclusion: The present study reports the antihypertensive activity of novel AT-1 receptor blocker FPD at 50 and 100 mg kg-1 with cGMP, L-type calcium channels, and BKCa channels as putative targets of vasorelaxation, and was found safe in oral toxicity.

A new synthetic biology approach for the production of curcumin and its glucoside in Atropa belladonna hairy roots.

Curcumin has ignited global interest as an elite drugable molecule, owing to its time-honoured pharmacological activities against diverse human ailments. Limited natural accessibility and poor oral bioavailability caused major hurdles in the curcumin-based drug development process. We report the first successful testimony of curcumin and its glucoside synthesis in Atropa belladonna hairy roots (HR) through metabolic engineering. Re-routing the inherent biosynthetic precursors of the phenylpropanoid pathway of A. belladonna by heterologous expression of key curcumin biosynthetic pathway genes (i.e., Diketide-CoA synthase-DCS and Curcumin synthase-CURS3) and glucosyltransferase gene (CaUGT2) resulted in the production of curcumin and its glucoside in HR clones. Under shake-flask cultivation, the PGD2-HR1clone bearing DCS/ CURS3 genes showed the maximum curcumin yield (180.62 ± 4.7 µg/g DW), while the highest content of curcumin monoglucoside (32.63 ± 2.27 µg/g DW) along with curcumin (67.89 ± 2.56 µg/g DW) were noted in the PGD3-HR3 clone co-expressing DCS/CURS3 and CaUGT2 genes. Bioreactor up-scaling showed yield improvements in the PGD2-HR1 (2.3 fold curcumin) and the PGD3-HR3 clone (0.9 and 1.65 folds of curcumin-monoglucoside and curcumin respectively). These findings proved the advantageous use of HR cultures as the production source for curcumin and its glucoside, which remained unexplored so far.

3-Arylindanones and related compounds as antiproliferative agents against colorectal cancer.

Diverse benzylidene indanones and their derivatives were synthesized as anticancer agents. Two of the analogues, that is 7 and 22, exhibited significant antiproliferative activity against several human cancer cell lines. Both the compounds possessed antimitotic activity and induced apoptosis in DLD1 colorectal adenocarcinoma cells through activation of caspase pathways. In cell cycle analysis, both the compounds induced predominantly G2/M phase arrest in DLD1 cells. Molecular docking studies revealed that compound 7 occupies colchicine binding pocket of ß-tubulin. Both the compounds were safe in acute oral toxicity in rodents. Both the compounds are further being optimized for better efficacy.

Synthesis of thymol-based pyrazolines: An effort to perceive novel potent-antimalarials.

A series of thymol based substituted pyrazolines and chalcones was synthesized and evaluated for antimalarial activity, using in-vitro and in-vivo malaria models. All the target compounds (5a-k and 6a-j) were found to be active against human malaria parasite strain Plasmodium falciparum NF54. Among all, compounds 5e and 5f of chalcone series and 6c and 6f of pyrazoline series exhibited prominent antimalarial activity with IC50 less than 3 and 2 µM respectively, while other pyrazolines also significantly inhibited the P. falciparum with IC50 less than 10 µM. The designed pharmacophores were found to be effective against P. falciparum. Compound 6f was found to be able to retard malaria progression in mice. This was evident through decreased parasitemia, increased mean survival time and hemoglobin content in the treated animals. Moreover, 6f was observed as an inhibitor of heme polymerization pathway of the malaria parasite. It also inhibited free heme degradation, which could be possibly responsible for higher reactive oxygen species (ROS) in parasite, thus inhibiting the rapid proliferation of the parasite. In addition to this, compound 6f was found to be non-toxic with a good selectivity index. Based on these observations, the compound 6f could be taken up for further antimalarial lead optimization studies.

Gallic acid-based indanone derivative interacts synergistically with tetracycline by inhibiting efflux pump in multidrug resistant E. coli.

The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.

Yield enhancement strategies for the production of picroliv from hairy root culture of Picrorhiza kurroa Royle ex Benth.

Fast-growing hairy root cultures of Picrorhiza kurroa induced by Agrobacterium rhizogenes offers a potential production system for iridoid glycosides. In present study we have investigated the effects of various nutrient medium formulations viz B5, MS, WP and NN, and sucrose concentrations (1-8%) on the biomass and glycoside production of selected clone (14-P) of P. kurroa hairy root. Full strength B5 medium was found to be most suitable for maximum biomass yield on the 40th day of culture (GI = 32.72 ± 0.44) followed by the NN medium of the same strength (GI = 22.9 ± 0.43). Secondary metabolite production was 1.1 and 1.3 times higher in half strength B5 medium respectively in comparison to MS medium. Maximum biomass accumulation along with the maximum picroliv content was achieved with 4% sucrose concentration in basal medium. RT vitamin and Thiamine-HCl effected the growth and secondary metabolite production of hairy roots growing on MS medium but did not show any effect on other media. The pH of the medium played significant role in growth and secondary metabolite production and was found to be highest at pH 6.0 while lowest at pH 3.0 and pH 8.0. To enhance the production of biomass and Picroliv 5 liter working capacity bioreactor was used, 27-fold (324 g FW) higher growth was observed in bioreactor than shake flask and secondary metabolite production was similarly enhanced.

Isolation, structure determination, and antiaging effects of 2,3-pentanediol from endophytic fungus of Curcuma amada and docking studies.

An endophytic fungus was isolated from the rhizomes of Curcuma amada (Zingiberaceae), which was identified as Fusarium oxysporum on the basis of its morphological and molecular characters. Chromatographic separation and spectroscopic analysis of the fungal metabolite (chloroform extract) led to the identification of one pure compound having molecular formula C5H12O2, i.e., 2,3-pentanediol (1). Activity analysis of compound 1 demonstrated improved antiaging (antioxidant, thermotolerance) properties against Caenorhabditis elegans, in comparison to a similar, commercially available molecule i.e., 1,5-pentanediol (2). The effective (lower) concentration of 1 significantly showed (28.6%) higher survival percentage of the worms under thermal stress (37 ºC) compared to its higher concentration (25.3%), while similar trends were followed in oxidative stress where (22.2%) higher survival percentage was recorded in comparison to untreated control. The compound 1, however, lacked potential antimicrobial activity, indicating the plausible ramification of the position of OH group in such bioactive molecules. In silico evaluation of these molecules against common as well as unique targets corroborated better antiaging potential of 1 in comparison to that of 2. The results for the first time indicated that the utilization of the endophytic fungi of C. amada could, thus, be a possible source for obtaining non-plant-based bioactive compounds having broader therapeutic applications pertaining to age-related progressions.

Tropine forming tropinone reductase gene from Withania somnifera (Ashwagandha): biochemical characteristics of the recombinant enzyme and novel physiological overtones of tissue-wide gene expression patterns.

Withania somnifera is one of the most reputed medicinal plants of Indian systems of medicine synthesizing diverse types of secondary metabolites such as withanolides, alkaloids, withanamides etc. Present study comprises cloning and E. coli over-expression of a tropinone reductase gene (WsTR-I) from W. somnifera, and elucidation of biochemical characteristics and physiological role of tropinone reductase enzyme in tropane alkaloid biosynthesis in aerial tissues of the plant. The recombinant enzyme was demonstrated to catalyze NADPH-dependent tropinone to tropine conversion step in tropane metabolism, through TLC, GC and GC-MS-MS analyses of the reaction product. The functionally active homodimeric ~60 kDa enzyme catalyzed the reaction in reversible manner at optimum pH 6.7. Catalytic kinetics of the enzyme favoured its forward reaction (tropine formation). Comparative 3-D models of landscape of the enzyme active site contours and tropinone binding site were also developed. Tissue-wide and ontogenic stage-wise assessment of WsTR-I transcript levels revealed constitutive expression of the gene with relatively lower abundance in berries and young leaves. The tissue profiles of WsTR-I expression matched those of tropine levels. The data suggest that, in W. somnifera, aerial tissues as well possess tropane alkaloid biosynthetic competence. In vivo feeding of U-[(14)C]-sucrose to orphan shoot (twigs) and [(14)C]-chasing revealed substantial radiolabel incorporation in tropinone and tropine, confirming the de novo synthesizing ability of the aerial tissues. This inherent independent ability heralds a conceptual novelty in the backdrop of classical view that these tissues acquire the alkaloids through transportation from roots rather than synthesis. The TR-I gene expression was found to be up-regulated on exposure to signal molecules (methyl jasmonate and salicylic acid) and on mechanical injury. The enzyme's catalytic and structural properties as well as gene expression profiles are discussed with respect to their physiological overtones.

Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents.

Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5 µg-mL(-1). In vitro cytotoxicity of compounds 16, 24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 times selective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective.

Atropa belladonna hairy roots: orchestration of concurrent oxidation and reduction reactions for biotransformation of carbonyl compounds.

The biotransformation potential of a selected Atropa belladonna hairy root clone (AB-09) had been evaluated with regard to three different aromatic carbonyl compounds, i.e., 3,4,5-trimethoxybenzaldehyde (1), 3,4,5-trimethoxyacetophenone (2), and 3,4,5-trimethoxy benzoic acid (3). The results demonstrated for the first time the untapped potentials of the selected hairy root clone to perform simultaneous oxidation (34.49%) and reduction (32.68%) of 3,4,5-trimethoxy benzaldehyde (1) into 3,4,5-trimethoxy benzoic acid (3), and 3,4,5-trimethoxy benzyl alcohol (4), respectively, without any intermediate separation or addition of reagents. The same hairy root clone also demonstrated reduction (<5%) of a 3,4,5-trimethoxyacetophenone (2) into a secondary alcohol, i.e., 1-(3,4,5-trimethoxyphenyl) ethanol (5), while in the case of aromatic carboxylic acid substrate (3), no biotransformation could be obtained under the similar conditions. The current observations revealed oxidation and reduction of the formyl group of the aromatic ring, and only reduction of the carbonyl group of acetophenone through the specific hairy root clone. The concurrent oxidation and reduction reactions by the selected hairy root clone highlight the importance of this study, which, as per our observations, is the first of its kind relating the hairy root culture of A. belladonna.

Pharmacophore modeling, molecular docking, QSAR, and in silico ADMET studies of gallic acid derivatives for immunomodulatory activity.

Immunomodulation refers to an alteration in the immune response due to the intrusion of foreign molecules into the body. In the present communication, QSAR and docking studies of gallic acid derivatives were performed in relation to their immunomodulatory activities. Screening through the use of a QSAR model suggested that the compounds G-4, G-7, G-9, G-10, G-12, and G-13 possess immunomodulatory activity. Activity was predicted using a statistical model developed by the forward stepwise multiple linear regression method. The correlation coefficient (r(2)) and the prediction accuracy (rCV(2)) of the QSAR model were 0.99 and 0.96, respectively. The QSAR study indicated that chemical descriptors-dipole moment, steric energy, amide group count, λ(max) (UV-visible) and molar refractivity-are well correlated with activity, while decreases in the dipole moment, steric energy, and molar refractivity were negatively correlated. A molecular docking study showed that the compounds had high binding affinities for the INFα-2, IL-6, and IL-4 receptors. Binding site residues formed H-bonds with the designed gallic acid derivatives G-3, G-4, G-5, G-6, G-7, and G-10. Moreover, based on screening for oral bioavailability, in silico ADME, and toxicity risk assessment, we concluded that compound G-7 exhibits marked immunomodulatory activity, comparable to levamisole.