A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles.

There has been developed an easy synthetic approach to spiro[dihydrofuran-2,3'-oxindoles] via a highly diastereoselective formal [4 + 1] cycloaddition reaction of [e]-fused 1H-pyrrole-2,3-diones with diazooxindoles. The described novel heterocyclic systems are heteroanalogues of antimicrobial and antibiofilm fungal metabolites. The developed reaction represents the first example of involving 1H-pyrrole-2,3-diones fused at the [e]-side in a [4 + 1] annulation reaction.

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.

Synthesis, in vitro antibacterial activity against Mycobacterium tuberculosis, and reverse docking-based target fishing of 1,4-benzoxazin-2-one derivatives.

Seventeen 1,4-benzoxazin-2-ones bearing the enaminone moiety and three of their analogs were tested for the antibacterial activity against Mycobacterium tuberculosis (H37Rv). Minimal bactericidal concentrations (MBCs) were determined after 41 days of incubation by BACTEC. 1,4-Benzoxazin-2-ones bearing the unsubstituted benzo moiety showed the most promising activities (MBC = 5.00 µg/ml). For most active compounds, antibacterial activities were determined daily during the 41 days. The most promising compound showed a bacteriostatic effect at a concentration of 0.31 µg/ml on Day 4 of incubation, 0.62 µg/ml on Day 6, 2.50 µg/ml on Day 9, and 5.00 µg/ml on Day 41. All studied compounds, along with some of their reported analogs, were docked to 35 proteins of M. tuberculosis to find their potent targets in these organisms. As a result of reverse docking, aspartate 1-decarboxylase, panD, was selected as the most appropriate target. Docking of the most active compounds to mutant panD from pyrazinamide-resistant strains of M. tuberculosis implies that they would not be active against these strains. Considering that most of pyrazinamide clinical resistance cases are due to loss-of-function mutations in pyrazinamidase, pncA, compounds from this study could be useful drugs for the treatment of some cases of pyrazinamide-resistant tuberculosis.

Organic Antifungal Drugs and Targets of Their Action.

In recent decades, there has been a significant increase in the number of fungal diseases. This is due to a wide spectrum of action, immunosuppressants and other group drugs. In terms of frequency, rapid spread and globality, fungal infections are approaching acute respiratory infections. Antimycotics are medicinal substances endorsed with fungicidal or fungistatic properties. For the treatment of fungal diseases, several groups of compounds are used that differ in their origin (natural or synthetic), molecular targets and mechanism of action, antifungal effect (fungicidal or fungistatic), indications for use (local or systemic infections), and methods of administration (parenteral, oral, outdoor). Several efforts have been made by various medicinal chemists around the world for the development of antifungal drugs with high efficacy with the least toxicity and maximum selectivity in the area of antifungal chemotherapy. The pharmacokinetic properties of the new antimycotics are also important: the ability to penetrate biological barriers, be absorbed and distributed in tissues and organs, get accumulated in tissues affected by micromycetes, undergo drug metabolism in the intestinal microflora and human organs, and in the kinetics of excretion from the body. There are several ways to search for new effective antimycotics: - Obtaining new derivatives of the already used classes of antimycotics with improved activity properties. - Screening of new chemical classes of synthetic antimycotic compounds. - Screening of natural compounds. - Identification of new unique molecular targets in the fungal cell. - Development of new compositions and dosage forms with effective delivery vehicles. The methods of informatics, bioinformatics, genomics and proteomics were extensively investigated for the development of new antimycotics. These techniques were employed in finding and identification of new molecular proteins in a fungal cell; in the determination of the selectivity of drugprotein interactions, evaluation of drug-drug interactions and synergism of drugs; determination of the structure-activity relationship (SAR) studies; determination of the molecular design of the most active, selective and safer drugs for the humans, animals and plants. In medical applications, the methods of information analysis and pharmacogenomics allow taking into account the individual phenotype of the patient, the level of expression of the targets of antifungal drugs when choosing antifungal agents and their dosage. This review article incorporates some of the most significant studies covering the basic structures and approaches for the synthesis of antifungal drugs and the directions for their further development.

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.

Synthesis of meta-substituted anilines via a three-component reaction of acetone, amines, and 1,3-diketones.

A facile method for the synthesis of meta-substituted arylamines from acyclic precursors was developed. This method is based on three-component cyclo-condensation/aromatization of in situ generated imines of acetone with 1,3-diketones either under conventional heating or under microwave irradiation. The utility of this methodology is illustrated by the possibility of a gram scale synthesis of various anilines from readily available reagents.

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.