Carbazoquinocin Analogues as Small Molecule Biomimetic Organocatalysts in Dehydrogenative Coupling of Amines.

A new series of carbazole-cored biomimetic ortho-quinone catalysts structurally resembling carbazoquinocin alkaloids have been introduced to promote tunable, metal cocatalyst-free, organocatalytic, dehydrogenative amine oxidation under aerobic conditions. Differently substituted benzyl amines were tolerated under optimized conditions to provide imines in excellent yields. Further efficacy of the catalyst was demonstrated by synthesizing cross-coupled imines efficiently. Control experiments and in-depth DFT studies disclosed a covalent transamination pathway as a plausible mechanism for this newly developed catalytic system.

Modular Total Synthesis of the 5/5-Spirocyclic Spiroindimicins.

Total syntheses of the 5/5-spirocyclic indoline alkaloids (±)-spiroindimicins B, C, D, E, F, and G have been achieved via a modular approach. Our route features direct coupling of halogenated pyrrolemetal and isatin partners, Suzuki coupling to append the indole unit, Lewis acid-mediated spirocyclization, and divergent functionalization to give various family members. These syntheses are concise (six or seven steps from commercial materials) and highly amenable to analogue synthesis.

Chronic musculoskeletal pain among elderly individuals in a rural area of West Bengal: A mixed-method study.

Introduction: The high prevalence among elderly individuals and potential adverse impact on their overall life quality make chronic musculoskeletal pain a significant public health concern. Chronic musculoskeletal pain is an important cause of self-medication, which must be addressed to avoid various side effects and improve elderly health. This study aimed to determine the prevalence of chronic musculoskeletal pain and its associated factors among individuals (age ≥60 years) in rural West Bengal and explore their perspectives and perceived barriers regarding pain and its management. Method: This mixed-method study was conducted in rural West Bengal from December 2021 to June 2022. The quantitative strand was conducted by interviewing 255 elderly participants (age ≥60 years) using a structured questionnaire. The qualitative strand was conducted via in-depth interviews of 10 patients with chronic pain. Quantitative data were analyzed using SPSS version 16, and chronic pain-related factors were analyzed using logistic regression models. Qualitative data were analyzed thematically. Results: Among the participants, 56.8% reported chronic musculoskeletal pain. The most frequently affected site was the knee joint. Comorbidity (adjusted odds ratio [aOR]=7.47, 95% confidence interval [CI]=3.2-17.5), age (aOR=5.16, 95% CI=2.2-13.5), depression (aOR=2.96, 95% CI=1.2-6.7) and over-the-counter drug usage (aOR=2.51, 95% CI=1.1-6.4) were significantly associated with chronic pain. Analgesic dependency, lack of motivation to adopt lifestyle modifications, lack of knowledge on analgesic side effects were considered pain management barriers. Conclusion: Managing comorbidities, providing mental support, generating awareness of analgesic side effects, strengthening healthcare facilities should be prioritized for holistic chronic musculoskeletal pain management.

Utilisation of adolescent reproductive and sexual health services in a rural area of West Bengal: A mixed-method study.

Introduction: Despite policy actions and strategic efforts for improving the reproductive and sexual health of adolescents by promoting the uptake of adolescent reproductive and sexual health (ARSH) services, the utilisation rate remains significantly low, especially in rural areas of India. This study aimed to assess the utilisation of these services by adolescents in rural West Bengal and its associated determinants. Method: This mixed-method study was conducted from May to September 2021 in the Gosaba rural block of South 24 Parganas, West Bengal. Quantitative data were collected from 326 adolescents using a pre-tested structured questionnaire. Qualitative data were collected via four focus group discussions among 30 adolescents and key-informant interviews among six healthcare workers. Quantitative data were analysed using SPSS, while qualitative data were analysed thematically. Results: Ninety-six (29.4%) adolescents had utilised ARSH services at least once during adolescence. The factors associated with non-utilisation of ARSH services were younger age, female sex, increasing reproductive health stigma and decreasing parent-adolescent communication related to sexual health. Qualitative exploration revealed that unawareness regarding services, perceived lack of privacy and confidentiality at healthcare facilities and disruption of services post-emergence of the COVID-19 pandemic were some major barriers to ARSH service utilisation. Conclusion: A multi-component strategy, including promotion of adolescent-friendly health clinics, community support interventions associated with motivation and counselling of parents regarding the importance of adolescent reproductive health, is needed to improve the utilisation of ARSH services. Necessary steps to correct the deficiencies at the facility level should also be prioritised.

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α1-antitrypsin-derived peptide motif.

Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α1-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.

Cascade Benzannulation Approach for the Syntheses of Lipocarbazoles, Carbazomycins, and Related Alkaloids.

Herein, a state-of-the-art one-pot cascade benzannulation technique for the efficacious synthesis of valuable 3-hydroxy-2-methyl carbazoles, a linchpin of more than 25 carbazole-based alkaloids, is unveiled from readily affordable fundamental commodities. The key step of this strategy is gaining aromaticity by site-selective elimination of hydroxyl group controlled by nucleophilicity of the indole ring. The present strategy shows excellent functional group tolerance with a broad substrate scope. The utility of this convenient approach was appealingly exemplified via concise total syntheses of 10 carbazole-based alkaloids possessing significant biological activities and thus of medicinal importance.

Synthesis of functionalized indoles via cascade benzannulation strategies: a decade's overview.

Indoles are one of the most prominent aromatic heterocycles in the organic chemistry field. Due to their widespread presence in various natural products, alkaloids, drugs, approved medicines, etc. the synthesis and functionalization of indoles are of great interest. This review emphasizes recent developments and techniques in the domino cascade cyclization process in the last decade starting from the various building blocks. In particular, this review depicts several intriguing benzannulation methods of creating a benzene ring on a pre-existing pyrrole nucleus in an inter/intramolecular fashion under metal-catalyzed/metal-free approaches. Different subsections focus on gradual timely developments in this complementary area and a detailed analysis of the mechanisms and reactivity patterns. As a complementary method, this review gives a significant incentive to various annulation strategies and also gives an overview of the remaining challenges and upcoming possibilities.

Determinants of Treatment Adherence Among Patients Living With Noncommunicable Diseases: A Mixed-Method Study in a Rural Area of West Bengal.

The multisectoral impact of the COVID-19 pandemic can impair treatment adherence of patients with noncommunicable diseases (NCDs). This mixed-method study, conducted from November 2020 to January 2021, assessed the quantum of their treatment adherence and its determinants in rural West Bengal. Quantitative data were collected from 213 NCD patients while qualitative exploration for barriers of treatment adherence was conducted as 6 in-depth Interviews. Treatment adherence was assessed by "Medication Compliance Questionnaire" and "Adherence to Healthy Lifestyle and Follow-up Advice" Questionnaire. A total of 39.4% were nonadherent to medications while 67.1% had nonadherence to healthy lifestyle and follow-up advice. Significant predictors associated with nonadherence were increasing age, female gender, lower socioeconomic status, decreasing patient empowerment, and decreasing trust in the medical profession. Economic crisis, fear of contagion, and nonavailability of investigation facilities were some new emerging barriers in addition to preexisting barriers of treatment adherence. Therefore, measures for improving patient empowerment and patient-provider relationship by motivation and counseling, taking proper care of vulnerable patients affected by the pandemic, and correcting deficiencies at the health-system level should be given utmost priority.

Cascade annulative π-extension for the rapid construction of carbazole based polyaromatic hydrocarbons.

A Brønsted acid catalyzed cascade benzannulation strategy for the one-pot synthesis of densely populated poly-aryl benzo[a]carbazole architectures is disclosed from easily affordable fundamental commodities. The efficacy of this technique was further validated via the concise synthesis of structurally unique carbazole based poly-aromatic hydrocarbons. Furthermore, the photo-physical properties of the synthesized compounds are thoroughly investigated.

Brønsted Acid-Catalyzed Tandem Pinacol-Type Rearrangement for the Synthesis of α-(3-Indolyl) Ketones by Using α-Hydroxy Aldehydes.

A Brønsted acid-catalyzed pinacol-type rearrangement pathway is reported here to synthesize various substituted α-(3-indolyl) ketones by employing unprotected indoles and α-hydroxy aldehydes as coupling partners. Utilization of economic and readily available Brønsted acid catalyst and use of simple starting precursors exemplify the economic viability of this method. Under this developed protocol, selective migration of aryl over alkyl or a second aryl group is observed depending upon the migratory aptitude of the substituents. Applicability of this method was further demonstrated by synthesizing highly substituted carbazoles through a simple extension of this method to one-pot cascade annulation strategy.

A Brønsted Acid Catalyzed Cascade Reaction for the Conversion of Indoles to α-(3-Indolyl) Ketones by Using 2-Benzyloxy Aldehydes.

A Brønsted acid catalyzed, operationally simple, scalable route to several functionalized α-(3-indolyl) ketones has been developed and the long-standing regioisomeric issue has been eliminated by choosing appropriate carbonyls. A readily available and cheap bottle reagent was used as the catalyst. This protocol was also applicable to the synthesis of densely functionalized α-(3-pyrrolyl) ketones. A detailed mechanistic study confirmed the involvement of enolether as a reaction intermediate. Several postsynthetic modifications along with easy access to ß-carboline, tryptamines, tryptophols, and spiro-indolenine proclaim the synthetic utility of this powerful building block. On the basis of this concept, functionalized carbazoles were constructed by a cascade annulation strategy.

Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model.

BACKGROUND: Trauma-associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration-approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off-target systemic coagulopathy, thromboembolic complications, and neuropathy. OBJECTIVE: We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot-stabilizing action site-selectively, to improve hemostasis and survival while avoiding off-target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen-mimetic peptide for anchorage to active platelets within trauma-associated clots, and encapsulated TXA within them. METHODS: The TXA-loaded trauma-targeted nanovesicles (T-tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA-loaded control (untargeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. RESULTS: Our studies show that in vitro, the T-tNVs could resist lysis in tPA-spiked rat blood. In vivo, T-tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma-targeted activity of the T-tNVs. CONCLUSION: Overall, the studies establish the potential of targeted TXA delivery for safe injury site-selective enhancement and stabilization of hemostatic clots to improve survival in trauma.

Formal [4 + 2] benzannulation of 2-alkenyl indoles with aldehydes: a route to structurally diverse carbazoles and bis-carbazoles.

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated. The sequence of four different reactions is executed in one-pot using readily available and cheap bottle reagents as catalysts rendering this method attractive. The incorporation of inexpensive and environmentally benign molecular oxygen as the oxidant into the final aromatization step enables tolerance of several functional groups.

Brønsted Acid Catalyzed One-Pot Benzannulation of 2-Alkenylindoles under Aerial Oxidation: A Route to Carbazoles and Indolo[2,3- a]carbazole Alkaloids.

A one-pot, protecting-group-free benzannulation of 2-alkenylindoles with readily available 1,3-dicarbonyls is demonstrated to construct structurally diverse carbazoles. The use of a cheap Brønsted acid catalyst and air as the sole oxidant exemplifies the economic viability of this protocol. The execution of four different reactions successively to generate the medicinally important indolocarbazole core is also achieved. This one-pot protecting-group-free method paved the way for the total synthesis of three medicinally important alkaloids, namely staurosporinone, arcyriaflavin A, and 7-hydroxy-K252c.

Transition-Metal-Free Redox-Neutral One-Pot C3-Alkenylation of Indoles Using Aldehydes.

The synthesis of sensitive ß-alkyl 3-vinylindoles having diverse functional groups with good selectivity remains a challenging task. Keeping the synthetic utility of 3-alkenylindoles in mind, we explored a unique approach to synthesize them from unprotected indoles in a domino fashion. A transition-metal-free C3-alkenylation of indole is reported by using sequential Brønsted acid/base catalysis. Several ß-substituted 3-alkenylindoles and conjugated 1,3-dienes are synthesized by direct coupling of indole and readily available aliphatic aldehydes. Excellent scalability and recycling of benzenesulfinic acid for successive alkenylation reactions up to five times make this method economically viable.

Organocatalytic asymmetric Michael addition of 1-acetylcyclohexene and 1-acetylcyclopentene to nitroolefins.

Enantioselective organocatalytic Michael addition reactions of 1-acetylcyclohexene, 1-acetylcyclopentene and 1-acetylcyclobutene to nitroolefins have been developed. This is the first report where an α-branched enone has been activated by an amine catalyst for the asymmetric Michael addition reaction to an electrophile. The Michael products have also been cyclized to bicyclic compounds.