Discovery of Natural Product Inspired 3-Phenyl-1H-isochromen-1-ones as Highly Potent Antioxidant and Antiplatelet Agents: Design, Synthesis, Biological Evaluation, SAR and In Silico Studies.

BACKGROUND: Several natural/synthetic molecules having a structure similar to 1H-isochromen- 1-ones have been reported to display promising antioxidants and platelet aggregation inhibitory activity. Isocoumarin (1H-2-benzopyran-1-one) skeleton, either whole or as a part of the molecular framework, has been explored for its antioxidant or antiplatelet activities. INTRODUCTION: Based on the literature, a new prototype, i.e., 3-phenyl-1H-isochromen-1-ones based compounds, has been rationalized to possess both antioxidant as well as antiplatelet activities. Consequently, no reports are available regarding its inhibition either by cyclooxygenase-1 (COX-1) enzyme or by arachidonic acid (AA)-induced platelet aggregation. This prompted us to investigate 3-phenyl-1H-isochromen-1-ones towards antioxidant and antiplatelet agents. METHODS: The goal of this work was to identify new 3-phenyl-1H-isochromen-1-ones based compounds via synthesis of a series of analogues, followed by performing in vitro antioxidant as well as AA-induced antiplatelet activities. Then, identification of potent compounds by SAR and molecular docking studies was carried out. RESULTS: Out of all synthesized 3-phenyl-1H-isochromen-1-ones analogues, five compounds showed 7-fold to 16-fold more highly potent antioxidant activities than ascorbic acid. Altogether, ten 3-phenyl-1H-isochromen- 1-one analogues displayed antioxidant activities in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Almost all the 3-phenyl-1H-isochromen-1-one analogues exhibited potent AA-induced antiplatelet activity; few of them displayed 7-folds more activity as compared to aspirin. Further, in silico analysis validated the wet results. CONCLUSION: We disclose the first detailed study for the identification of 3-phenyl-1H-isochromen-1-one analogues as highly potent antioxidant as well as antiplatelet agents. The article describes the scaffold designing, synthesis, bioevaluation, structure-activity relationship, and in silico studies of a pharmaceutically privileged bioactive 3-phenyl-1H-isochromen-1-one class of heterocycles.

Nanoparticles Mediated Target-specific Drug Delivery in Prostate Cancer: An In-depth Review.

Nanotechnology has been extensively exploited for its enormous therapeutic and diagnostic potential in the management of multiple disorders. It employs nanomaterials as drug carriers with enhanced efficacy and limited side effects on normal tissues. A lot of nanomaterials have been studied and produced, imminently reforming the treatment and diagnostics of numerous malignancies, including cancer. The purpose of the present study is to explore the role of nanotechnology-based devices/therapies that have a vital function in the therapeutics and diagnostics of cancer with potential impact at three levels: early detection, tumor imaging, and drug delivery methods. Concentrating on cancer, promising nanotechnology-based approaches have been planned to satisfy the need for targeted specificity of traditional agents of chemotherapeutics, in addition to early recognition of malignant and precancerous lesions. Prostate cancer is the fifth most wellknown cancer worldwide and the second most usually detected cancer in men. Therefore, there is a crucial need to improve therapeutic prospects for the diagnosis and treatment of prostate cancer via the exploitation of the potential of nanomaterials for cell-targeted specificity and improved primary diagnosis of precancerous tumors. The present review, therefore, focuses on summarizing all prospective applications of nanotechnology in the prognosis and diagnosis of prostate cancer, which would further help researchers to elucidate a more potent therapeutic approach for the better management of prostate cancer in the days ahead.

Current update on psyllium and alginate incorporate for interpenetrating polymer network (IPN) and their biomedical applications.

Natural polysaccharides and their designed structures are extremely valuable due to their intrinsic pharmacological properties and are also used as pharmaceutical aids. These naturally occurring polysaccharides (e.g., psyllium and alginate) are gaining popularity for their use in the preparation of interpenetrating polymer network (IPN) materials with improved swelling ability, biodegradability, stability, non-cytotoxic, biocompatibility, and cost-effectiveness. IPN is prepared sequentially or simultaneously by microwave irradiation, casting evaporation, emulsification cross-linking, miniemulsion/inverse miniemulsion technique, and radiation polymerization methods. In addition, the prepared IPNs have has been extensively characterized using various analytical and imaging techniques before sustainable deployment for multiple applications. Regardless of these multi-characteristic attributes, the current literature lacks a detailed overview of the biomedical aspects of psyllium, alginate, and their engineered IPN structures. Herein, we highlight the unique synthesis, structural, and biomedical considerations of psyllium, alginate, and engineered IPN structures. In this review, a wide range of biomedical applications, such as role as a drug carrier for sustain delivery, wound dressing, tissue engineering, and related miscellaneous application of psyllium, alginate, and their IPN structures described with appropriate examples. Further research will be carried out for the development of IPN using psyllium and alginate, which will be a smart and active carrier for drugs used in the treatment of life-threatening diseases due to their inherent pharmacological potential such as hypoglycemic, immunomodulatory, antineoplastic, and antimicrobial.

Microwave-assisted modified synthesis of C8-analogues of naturally occurring methylxanthines: Synthesis, biological evaluation and their practical applications.

An efficient, microwave-assisted, oxidant-interceded, transition-metal-free, cross-dehydrogenative Csp2-Csp3 coupling of C8-Caffeine 2/Theobromine 3/theophylline 4 with substituted aliphatic alcohols 11a-lvia CH bond activation for the preparation of series of substituted C8-(hydroxymethyl) Caffeine 12a-l/theobromine 13a-c/theophylline 14a-b has been developed using microwave irradiation upto 98% yield. The reaction proceeds smoothly in the presence of tert-butyl hydroperoxide (TBHP) under solvolysis condition at 120 °C for 20 min to corresponding substituted C8-(hydroxymethyl)-methylxanthine derivatives in good to excellent yields. The good substrate scope, control experiments, gram-scale synthesis, and practical synthetic transformations further highlights the practicality of this methodology. These C8-(hydroxymethyl) Caffeine 12a-l, 13a-c and 14a-b have been found to show promising in vitro antioxidant as well as antiplatelet activities.

Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-benzylideneisobenzofuran-1(3H)-ones as Highly Potent antioxidants and Antiplatelet agents.

For the first time, a series of highly potent natural product inspired substituted (Z)-3-benzylideneisobenzofuran-1(3H)-ones 28a-t, embraced with electron-withdrawing groups (EWG) and electron-donating groups (EDG) at site I and site II, were prepared and assessed for their in vitro antioxidant activities (DPPH free radical scavenging assay) and arachidonic acid (AA)-induced antiplatelet activities using ascorbic acid (IC50 = 4.57 µg/mL) and aspirin (IC50 = 21.34 µg/mL), as standard references, respectively. In this study, compounds 28f-g, 28k-l and 28q have shown high order of in vitro antioxidant activity. Infact, 28f and 28k were found to show 10-folds and 8-folds more antioxidant activity than ascorbic acid, respectively and was found to be the most active analogues of the series. Similarly, Compounds 28c-g, 28k-l, 28o and 28q-t were recognized as highly potent antiplatelet agents (upto 6-folds) than aspirin. Furthermore, in silico studies of the most active antioxidants 28f, 28k and 28l and very active antiplatelet molecules 28f, 28k, 28l and 28s were carrying out for the validation of the biological results. This is the first detailed study of the discovery of several (Z)-3-benzylideneisobenzofuran-1(3H)-ones as highly potent antioxidants and antiplatelet agents.

Antimicrobial studies, synthesis and characterization of novel 1-nitro-10H-phenothiazine bearing sulfone/nucleoside moieties.

The current research article involves one pot synthesis of novel substituted 1-nitro-10H-phenothiazines via Smiles rearrangement. These substituted phenothiazines undergo oxidation to yield 10H-phenothiazine-5,5-dioxides (sulfones) while on treatment with ß-D-ribofuranose-1-acetate-2,3,5-tribenzoate yield ribofuranosides. These compounds were screened for their antimicrobial vitalities (in vitro) against selected strains of bacteria and fungi. The characterization of synthesized compounds was done by elemental and spectral studies.

Organocatalytic Modified Guareschi-Thorpe Type Regioselective Synthesis: A Unified Direct Access to 5,6,7,8-Tetrahydroquinolines and Other Alicyclic[ b]-Fused Pyridines.

An unprecedented organocatalytic, regioselective, modified Guareschi-Thorpe type protocol toward the modular synthesis of 5,6,7,8-tetrahydroquinolines 22a-g and other alicyclic[ b]-fused pyridines 23-28 via the identification of Chitosan as a heterogeneous catalyst is reported. This novel strategy is operationally simple and showed a wide range of functional group tolerance and substrate compatibility. The proposed mechanistic pathway involves an imine-enamine cascade approach for the synthesis of structurally diverse alicyclic[ b]-fused pyridine heterocycles. The gram scale synthesis and identification of a new class of antifungal molecules 29-31 emphasize the practicality of this method.

Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure-Activity Relationships, Biological Evaluations, and in†silico Molecular Docking Studies.

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH3 , OC2 H5 , OC3 H7 ) functional groups at C1/C2 of ring A and an acyl (COCH3 and COPh) or phenylsulfonyl (SO2 Ph and SO2 C6 H4 -3-CH3 ) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)-induced antiplatelet aggregation inhibitory activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure-activity relationship related to AA-induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone to be the best compounds of the series. Moreover, the DPPH free-radical-scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed.

An efficient synthesis and biological evaluation of novel analogues of natural product Cephalandole A: A new class of antimicrobial and antiplatelet agents.

Cephalandole A 2, a small indole alkaloid isolated from the Taiwanese orchid Cephalanceropsis gracilis (Orchidaceae), exhibits anticancer activity. Surprisingly, this natural product has not been evaluated for any other biological activity so far. To discover other novel potential of Cephalandole A 2, an efficient and economic synthetic protocol for novel Cephalandole A analogues 21a-o has been developed, in only 3 steps from using indole, and applied for their biological activity. Biological testing showed that Cephalandole A 2 and its novel analogues 21a-o exhibited potential antimicrobial and antiplatelet activity in preliminary assay. To the best of our knowledge, this is the first report of Cephalandole A 2 and its novel synthetic analogues 21a-o as a new class of antimicrobial and antiplatelet agents. In this study, 2 and other analogues i.e., 21b, 21d, 21i and 21o showed promising antimicrobial activity against the phytopathogenic bacteria and fungi. Cephalandole A 2, 21c, 21f and 21i, also showed potent antiplatelet activity.

Discovery of C-3 Tethered 2-oxo-benzo[1,4]oxazines as Potent Antioxidants: Bio-Inspired Based Design, Synthesis, Biological Evaluation, Cytotoxic, and in Silico Molecular Docking Studies.

The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs 20a-20ab have been synthesized via "on water" ultrasound-assisted irradiation conditions in excellent yields (upto 98%). All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC50 values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 µg/mL taking ascorbic acid (IC50 = 4.57 µg/mL) as standard reference. In this study, compounds 20b and 20t, the most active compound of the series, showed IC50 values of 6.89 ± 0.07 µg/mL and 4.74 ± 0.08 µg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (20c, 20j, 20m, 20n, 20r, 20u, 20z, and 20aa) were found more potent than standard reference BHT (C0.5FRAP = 546.0 ± 13.6 µM). The preliminary cytotoxic study reveals the non-toxic nature of active compounds 20b and 20t in non-cancerous 3T3 fibroblast cell lines in MTT assay up to 250 µg/mL concentration. The results were validated via carrying out in silico molecular docking studies of promising compounds 20a, 20b, and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.

Non-peptide-based new class of platelet aggregation inhibitors: Design, synthesis, bioevaluation, SAR, and in silico studies.

A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a-x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC50 = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T3 fibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18i, 18l, and 18o) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non-peptide-based functionalized 2-oxo-benzo[1,4]oxazines as platelet aggregation inhibitors.

Synthesis, antimicrobial activity, structure-activity relationship and cytotoxic studies of a new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones.

A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23-26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(-)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c-e, 24e, 25d and 26d-e found to be non-toxic in nature in 3T3 fibroblast cell lines using MTT assay.

Microwave-assisted One-pot Efficient Synthesis of Functionalized 2-Oxo-2-phenylethylidenes-linked 2-Oxobenzo[1,4]oxazines and 2-Oxoquino[1,4]oxalines: Synthetic Applications, Antioxidant Activity, SAR and Cytotoxic Studies.

A microwave-assisted, environmentally benign green protocol for the synthesis of functionalized (Z)-3-(2-oxo-2-phenylethylidene)-3, 4-dihydro-2H-benzo[b][1,4]oxazin-2-ones (11a-n) in excellent yields (upto 97%) and (Z)-3-(2-oxo-2-phenylethylidene)-3,4-dihydroquinoxalin-2(1H)-ones (14a-h) (upto 96% yield) are reported. The practical applicability of developed methodology were also confirmed by the gram scale synthesis of 11a, 14c and 14e; synthesis of anticancer alkaloid Cephalandole A 16 (89% yield). All the synthesized compounds 11a-n, 14a-h and 16 were assessed for their in vitro antioxidant activities in DPPH radical scavenging and FRAP assay. In DPPH assay, compounds 11a, 14c and 14e, the most active compounds of the series, were found to show IC50 value of 10.20 ± 0.08 µg/mL, 9.89 ± 0.15 µg/mL and 8.97 ± 0.13 µg/mL, respectively in comparison with standard reference (ascorbic acid, IC50 = 4.57 µg/mL). Whereas, in FRAP antioxidant assay seven compounds (11c, 11e, 11i, 11k, 11l, 14d and 14h) displayed higher antioxidant activity in comparison to the reference standard BHT (C0.5FRAP = 546.2 µM). Moreover, the cytotoxic studies of the compounds 11a, 14c, 14e and 14h were found to be non-toxic in nature in 3T3 fibroblast cell lines using MTT assay.

Studies on trigonelline from Moringa oleifera and its in vitro regulation by feeding precursor in cell cultures

Trigonelline (N-methylnicotinate) biosynthesized from nicotinate is one of the metabolically active pyridine alkaloid, widely distributed in plant kingdom. In the present study trigonelline has been isolated from various plant parts and callus cultures of Moringa oleifera Lam., Moringaceae, and was identified using TLC, GLC, GC-MS, which was comparable to that of the standard trigonelline. The trigonelline recovery was found to be maximum in the pods and minimum in flowers. In order to enhance the production of trigonelline in vitro grown cultures, different treatment doses of nicotinic acid (250, 500 and 750 mg L-1) were supplemented in the medium as precursor. Maximum increase (up to 1.10 fold) was observed in the treatment dose of 500 mg L-1 of nicotinic acid.

Antiradical efficiency of 20 selected medicinal plants.

The antioxidant system of a plant comprises a group of chemicals that are highly diverse in their sources, effects and uses. These antioxidants are capable of contracting and damaging free radicals. This investigation deals with a screening and comparison of the antioxidant activities of 20 selected medicinal plants and their parts, individually and in combination with vitamins A, C or E, using the DPPH radical scavenging method. Phyllanthus emblica L., Santalum album L., Syzygium cumini L. and Trigonella foenum-graecum L. presented highly significant antiradical efficiency (AE) singly and in combination with either vitamin A, C or E. Further, Curcuma longa L., Momordica charantia L., S. cumini, T. foenum-graecum, Moringa oleifera Lam and S. album have also shown fairly significant AE in a vitamin combination dose of 0.001 mM concentration.

Evaluation of antidiabetic and antioxidant activity of Moringa oleifera in experimental diabetes.

BACKGROUND: Moringa oleifera, a widely cultivated species in India, is an exceptionally nutritious vegetable with a variety of potential uses in treating rheumatism, venomous bites, and microbial infections. In the present study, we investigated the antidiabetic and antioxidant effects of methanol extracts of M. oleifera pods (MOMtE) in streptozotocin (STZ)-induced diabetic albino rats. METHODS: Diabetic rats were treated with 150 or 300 mg/kg MOMtE for 21 days and the antidiabetic effects of the extract were evaluated by measuring changes in biochemical parameters in the serum and pancreatic tissue. Two phytoconstituents, namely quercetin and kaempferol, were isolated from the MOMtE extract and their structures were determined using nuclear magnetic resonance and infrared spectroscopy. RESULTS: The progression of diabetes was significantly reduced after MOMtE treatment. In treated rats, both doses of MOMtE induced a significant reduction in serum glucose and nitric oxide, with concomitant increases in serum insulin and protein levels. Furthermore, MOMtE treatment increased antioxidant levels in pancreatic tissue, with concomitant decreases in levels of thiobarbituric acid-reactive substances. Histologic examination of the pancreas from diabetic rats showed degenerative changes in ß-cells; MOMtE treatment significantly reversed the histoarchitectural damage to the islets cells. CONCLUSION: In conclusion, M. oleifera exerts protective effects against STZ-induced diabetes. The MOMtE exhibited significant antidiabetic and antioxidant activity and active constituents may be isolated from the extract for evaluation in future clinical studies.