Developments in the stereoselective synthesis of benzopyran, benzopyrone and flavonoid based natural product analogues using C-glycosides as an intrinsic chiral synthon.

Stereoselective synthesis is essential for propelling mainstream academia toward a relentless pursuit of novel and cutting-edge strategies for constructing molecules with unparalleled precision. Naturally derived benzopyrans, benzopyrones, and flavonoids are an essentially prominent group of oxa-heterocycles, highly significant targets in medicinal chemistry owing to their extensive abundance in biologically active natural products and pharmaceuticals. The molecular complexity and stereoselectivity induced by heterocycles embedded with C-glycosides have attracted considerable interest and emerged as a fascinating area of research for synthetic organic chemists. This present article emphasizes the existing growths in the strategies involving the diastereoselective synthesis of C-glycosylated benzopyrans, benzopyrones, and flavonoids using naturally acquired glycones as chiral synthons.

Benzopyrone, a privileged scaffold in drug discovery: An overview of FDA-approved drugs and clinical candidates.

Natural products have always served as an important source of drugs for treating various diseases. Among various privileged natural product scaffolds, the benzopyrone class of compounds has a substantial presence among biologically active compounds. One of the pioneering anticoagulant drugs, warfarin approved in 1954 bears a benzo-α-pyrone (coumarin) nucleus. The widely investigated psoriasis drugs, methoxsalen, and trioxsalen, also contain a benzo-α-pyrone nucleus. Benzo-γ-pyrone (chromone) containing drugs, cromoglic acid, and pranlukast were approved as treatments for asthma in 1982 and 2007, respectively. Numerous other small molecules with a benzopyrone core are under clinical investigation. The present review discusses the discovery, absorption, distribution, metabolism, excretion properties, and synthetic approaches for the Food and Drug Administration-approved and clinical-stage benzopyrone class of compounds. The role of the pyrone core in biological activity has also been discussed. The present review unravels the potential of benzopyrone core in medicinal chemistry and drug development.

Efficacy and Safety of the Phytochemical Product Linfadren in the Management of Patients With Persistent Ankle Edema Following Trauma or Surgery: A Randomized Controlled Trial.

BACKGROUND: Persistent posttraumatic/postsurgery ankle edema (PPAE) is edema that persists from 2 weeks to 3 months after injury or surgery. PPAE has negative effects on the healing process and quality of life. This study aimed to evaluate the efficacy of a phytochemical product containing diosmin, coumarin, and arbutin (Linfadren) in addition to the conventional treatment, in patients with PPAE. METHODS: Between October 2018 and February 2020, 60 outpatients with PPAE (42 with ankle fractures and 18 with ankle sprains) were enrolled and randomized (1:1 ratio) to receive either 6-week conventional treatment plus Linfadren (study group) or conventional treatment alone (control group). Primary outcome was ankle edema as measured by the "figure-of-8-20" method. Secondary outcomes were ankle function measured by the Lower Extremity Functional Scale (LEFS), and patient's overall perceived treatment efficacy. Tolerability of Linfadren was also evaluated. Assessments were performed at baseline, at end of treatment (6 weeks after baseline), and 3 months after the end of treatment (follow-up). A subgroup analysis was also conducted for the injury type (fracture/sprain) to identify if this factor affected the results of the primary outcome measure. RESULTS: At the end of treatment, the study group had a significantly greater improvement in ankle edema, improved ankle function, and more patients who considered this treatment effective compared with the control group. The measured difference in circumference by the figure-of-8-20 method averaged 4% at 6 weeks and 5% at 3 months. No difference between groups was seen in rescue medication. No adverse events were recorded. Subgroup analysis revealed no significant influence of the injury type on the primary outcome measure. CONCLUSION: Linfadren in addition to conventional treatment was more effective than conventional treatment alone in patients with PPAE. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Bioisosterism in Drug Discovery and Development - An Overview.

Bioisosterism is a unique approach used by medicinal chemists for the reasonable modification of lead compounds into safer, more clinically effective, economical, and therapeutically attractive drugs. It is one of the most crucial lead modification tools, widely applied in the field of rational drug design to amplify the desired activity and eliminate undesirable properties, thus facilitating the optimization of pharmacokinetic profile and achievement of target selectivity. This review demonstrates the importance of bioisosterism in the process of drug discovery and development and highlights its relevance in the molecular evolution of many classes of drugs such as antibacterial sulfonamides, anticancer drugs, antivirals, antifungals, anthelmintics, local anesthetics, barbiturates, antidepressants, antihistamines, proton pump inhibitors and work carried out by our team of researchers. The role of bioisosterism as a strategy to achieve inhibition of enzymes such as thymidylate synthase, DNA polymerase, reverse transcriptase and several others has also been pointed out. There are no limits to the classes of drugs where bioisosterism has been successfully applied.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms.

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom.

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin (benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment in the management of patients with post-trauma/surgery persistent hand edema: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness and safety of oral administration of Linfadren® in addition to conventional treatment in patients with post-trauma/surgery persistent hand edema. DESIGN: Parallel-group randomized controlled trial. SETTING: Outpatient rehabilitation center. SUBJECTS: A total of 60 outpatients (mean age 48.5 (standard deviation (SD) = 12.3) years) with post-trauma/surgery persistent hand edema. INTERVENTIONS: Patients were randomized to either receive six-week conventional treatment plus Linfadren® (Study Group) or conventional treatment (Control Group). MAIN MEASURES: Primary outcome was hand edema as measured by figure-of-eight method. Secondary outcomes were hand function, patient's overall perceived treatment effectiveness and rescue medication request. Tolerability of Linfadren® was also evaluated. Assessments were performed at baseline, at the end of treatment and three months after the end of treatment. RESULTS: All patients completed the six-week program and 57 patients (95%) completed the three-month follow-up. At six weeks, the Study Group had significantly greater improvement in hand edema (423.3 (SD = 23.8) mm vs 439.4 (SD = 22.6) mm; P = 0.009) and upper limb function ( Quick Disabilities of Arm, Shoulder and Hand questionnaire: 23.6 (SD = 13.6) vs 37.7 (SD = 15.9); P = 0.005) compared to the Control Group. Moreover, the percentage of patients who perceived treatment as effective was significantly higher in the Study Group than in the Control Group both after treatment (70% vs 37%, P = 0.002) and at follow-up (77% vs 30%, P < 0.0001). The rescue medication request was not different between groups. No adverse events were recorded. CONCLUSION: Linfadren® in addition to conventional treatment was safe and more effective than conventional treatment alone in patients with post-trauma/surgery persistent hand edema.

Melilotus, Rutin and Bromelain in primary and secondary lymphedema.

As reported in the literature, benzopyrones (alpha and gamma) have important effects on the microcirculation through various mechanisms. Coumarins are an alpha-benzopyrone as derivatives of Melilotus Officinalis, while bioflavonoids are a gamma-benzopyrone and include Rutin. Alpha-benzopyrones have two fundamental pharmacological effects: they have pro-lymphokinetic action by activating contractility of lymphangions; and the activation of macrophages to provide a proteolytic effect. Gamma-benzopyrones, such as Rutin, have an important anti-exuding and membrane stabilizing effect. Bromelain is known for its anti-inflammatory effect. The present study enrolled 52 patients with primary and/or secondary lymphedema in clinical stages I or II (according to the ISL classification) with 31 cases involving the lower limbs and 21 cases involving the upper limbs. All subjects were given for six months a natural compound consisting of 100 mg of natural Melilotus, that contains 20 grams of Coumarin, 300 mg of Rutin and 100 mg of Bromelain. The following parameters were studied at zero time (T0), after three months (T1), and after six months of treatment (T2): pitting, Stemmer's sign, measurement of limb circumferences, measurement of superficial tissue thickness in the affected limbs using ultrasound, and blood tests to evaluate hepatic function (ALT, AST, GGT, total and fractional bilirubin). At the end of the treatment (T2), the following results were observed: disappearance of pitting in 72% of the cases; unchanged Stemmer's sign; average decrease in limb circumferences of 4.2 cm; and average reduction of the superficial thickness of 29%. There was no variation in the liver function parameters examined. The combination of natural compounds (Melilotus, Rutin, and Bromelain) has been shown to be a valuable aid in the clinical control of both primary and secondary lymphedema of clinical stages I and II as well as in control of inflammatory phenomena related to chronic stasis. There were no side effects and no alteration of liver function parameters found.

Scaffold Diversity Synthesis Delivers Complex, Structurally, and Functionally Distinct Tetracyclic Benzopyrones.

Complexity-generating chemical transformations that afford novel molecular scaffolds enriched in sp3 character are highly desired. Here, we present a highly stereoselective scaffold diversity synthesis approach that utilizes cascade double-annulation reactions of diverse pairs of zwitterionic and non-zwitterionic partners with 3-formylchromones to generate highly complex tetracyclic benzopyrones. Each pair of annulation partners adds to the common chroman-4-one scaffold to build two new rings, supporting up to four contiguous chiral centers that include an all-carbon quaternary center. Differently ring-fused benzopyrones display different biological activities, thus demonstrating their immense potential in medicinal chemistry and chemical biology research.

Synthesis and Anticancer Evaluation of Some New 3-Benzyl-4,8-Dimethylbenzopyrone Derivatives.

INTRODUCTION: New benzopyrone derivatives such as Schiff's like compounds, acetohydrazides or substituted with oxadiazole or pyrazole heterocycles were synthesized from parent acid hydrazide compound 3. METHODS AND MATERIALS: Structures of the synthesized compounds were elucidated using IR, NMR and mass spectroscopy. All the synthesized derivatives were selected by National Cancer Institute (NCI), Bethesda, and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay. RESULTS AND CONCLUSION: Schiffs like compounds 4a, b and c were found to have good growth inhibition % against numerous cell lines that belong mainly to leukemia, non-small cell lung, CNS and breast Cancer subpanels.

[Drug Treatment of Chronic Venous Diesease]. / Medikamentöse Behandlung chronischer Venenerkrankungen.

Chronic venous disease (CVD) affects at least 15-25 % of the general population incurring not only high morbidity but also considerable economical burden. The mainstay of modern treatment of CVD are endovenous therapeutic procedures and compression therapy. As far as the pathogenesis of CVD is being gradually unraveled the interest in drugs able to impact the process is growing. Here we have presented an overview of a majority of oral preparations used so far to treat CVD including venous leg ulcers. After several decades of clinical use a few flavonoid preparations, in the first place micronized purified flavonoid fraction, collected enough evidence to recommend them as a short-term adjunct treatment of CVD. However, other compounds are also promising in this regards. Yet, we need more larger and longer-term clinical trials to more precisely define effects, cost-effectiveness and, above all, capacity for prophylactic application of the drugs. Learning more about basis of CVD will help design new drugs directed at specific aspects of the disease process.

Synthesis, docking and in vitro anticancer evaluation of some new benzopyrone derivatives.

The synthesis of some new 3-alkyl-7-hydroxy-4-methyl-8-substituted-1H-benzopyran-2-ones, 6-alkyl-7-methyl-2-substituted amino-5H-pyrano[6,5-e] benzoxazol-5-ones, 7-alkyl-8-methyl-3-substituted-2,6-dihydropyrano[6,5-f]-1,4-benzoxazin-6-ones, 7,8-disubstituted-3-ethyl-4-methyl-1H-benzopyran-2-ones and 3-alkyl-4-methyl-7-substituted-1H-benzopyran-2-ones were described. Fourteen compounds were selected by National Cancer Institute (NCI), Bethesda, and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay by a single dose test. Compounds 4a, 18a, 18b and 23a were found to be broad-spectrum antitumors showing effectiveness toward numerous cell lines that belong to different tumor subpanels. Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the binding site of the casein kinase II (CK2) enzyme which is involved in cell survival and proliferation through a number of downstream effectors.