Anticancer and chemopreventive potential of Morinda citrifolia L. bioactive compounds: A comprehensive update.

Morinda citrifolia L., commonly known as Noni, has a longstanding history in traditional medicine for treating various diseases. Recently, there has been an increased focus on exploring Noni extracts and phytoconstituents, particularly for their effectiveness against cancers such as lung, esophageal, liver, and breast cancer, and their potential in cancer chemoprevention. This study aims to provide a comprehensive review of in vitro and in vivo studies assessing Noni's impact on cancer, alongside an exploration of its bioactive compounds. A systematic review was conducted, encompassing a wide range of scientific databases to gather pertinent literature. This review focused on in vitro and in vivo studies, as well as clinical trials that explore the effects of Noni fruit and its phytoconstituents-including anthraquinones, flavonoids, sugar derivatives, and neolignans-on cancer. The search was meticulously structured around specific keywords and criteria to ensure a thorough analysis. The compiled studies highlight Noni's multifaceted role in cancer therapy, showcasing its various bioactive components and their modes of action. This includes mechanisms such as apoptosis induction, cell cycle arrest, antiangiogenesis, and immune system modulation, demonstrating significant anticancer and chemopreventive potential. The findings reinforce Noni's potential as a safe and effective option in cancer prevention and treatment. This review underscores the need for further research into Noni's anticancer properties, with the hope of stimulating additional studies and clinical trials to validate and expand upon these promising findings.

Synthesis and biological profile of benzoxazolone derivatives.

The benzoxazolone nucleus is an ideal scaffold for drug design, owing to its discrete physicochemical profile, bioisosteric preference over pharmacokinetically weaker moieties, weakly acidic behavior, presence of both lipophilic and hydrophilic fragments on a single framework, and a wider choice of chemical modification on the benzene and oxazolone rings. These properties apparently influence the interactions of benzoxazolone-based derivatives with their respective biological targets. Hence, the benzoxazolone ring is implicated in the synthesis and development of pharmaceuticals with a diverse biological profile ranging from anticancer, analgesics, insecticides, anti-inflammatory, and neuroprotective agents. This has further led to the commercialization of several benzoxazolone-based molecules and a few others under clinical trials. Nevertheless, the SAR exploration of benzoxazolone derivatives for the identification of potential "hits" followed by the screening of "leads" provides a plethora of opportunities for further exploration of the pharmacological profile of the benzoxazolone nucleus. In this review, we aim to present the biological profile of different derivatives based on the benzoxazolone framework.

Hybridization of antimicrobial oxazolidinones with commercial drugs: A fight against the "superbugs".

Antimicrobial resistance caused by the emergence of antibiotic-resistant microbes, termed as "superbugs," poses a grave healthcare concern in the contemporary era. Though this phenomenon is natural, an incessant use of antibiotics due to their unregulated over-the-counter availability, and a lack of compliance with the legislation seem to be major contributing factors. This phenomenon has further complicated the treatment of common infectious diseases thereby leading to prolonged illness, disability, and even death. In addition, a sizeable impact on the healthcare cost is met due to a prolonged stay at the medical facilities to receive an intensive care. Overall, the gains of "Millennium Development Goals" and the accomplishment of Sustainable Development Goals are at risk due to the emerging antimicrobial resistance. Since an early identification and development of novel antibiotic classes that evade antimicrobial resistance appears improbable, the strategy of hybridization of the existing antibiotics with efficacious pharmacophores and drug molecules with a different mechanism of antimicrobial action can be a silver lining for the management of superbugs. In this regard, we aim to provide a perspective for the applicability of the hybridization of oxazolidinone class of antibiotics with other drugs for evading antimicrobial resistance.

Cyclic carbamates in medicine: A clinical perspective.

Carbamate group is mainly used for designing prodrugs to achieve first-pass and systemic stability against enzyme hydrolysis as the carbamate functionality is recognized by esterase enzymes. As compared to the ester functionality, the carbamate group shows a lesser lability towards enzyme hydrolysis, but a higher susceptibility than amides. Cyclic carbamates present a unique motif in the contemporary drug discovery and development owing to the presence of a polar, and sterically small, constrained Hydrogen-bonding acceptor atom. The metabolic stability of 5/6-membered cyclic carbamates are higher as compared to their acyclic counterparts as the former do not undergo metabolic ring opening under physiological conditions. Besides, the metabolic lability of acyclic carbamates is determined by the degree of substitution at the endocyclic/exocyclic "N" atom, which further enables the design and development of various carbamate drugs or prodrugs. As such, the metabolic stability of carbamates follows the order: Cyclic carbamates > Alkyl-OCO-NH2 ¼ Alkyl-OCO-NHAcyl ∼ Alkyl-OCO-NHAryl ≥ Aryl-OCO-N(endocyclic) ∼ Aryl-OCO-N(Alkyl)2 ≥ Alkyl-OCO-N(endocyclic) ≥ Alkyl-OCO-N(Alkyl)2 ∼ Alkyl-OCO-NHAlkyl ¼ Aryl-OCO-NHAlkyl.

Luteolin: a flavonoid with a multifaceted anticancer potential.

Therapeutic effect of phytochemicals has been emphasized in the traditional medicine owing to the presence of bioactive molecules, such as polyphenols. Luteolin is a flavone belonging to the flavonoid class of polyphenolic phytochemicals with healing effect on hypertension, inflammatory disorders, and cancer due to its action as pro-oxidants and antioxidants. The anticancer profile of luteolin is of interest due to the toxic effect of contemporary chemotherapy paradigm, leading to the pressing need for the development and identification of physiologically benevolent anticancer agents and molecules. Luteolin exerts anticancer activity by downregulation of key regulatory pathways associated with oncogenesis, in addition to the induction of oxidative stress, cell cycle arrest, upregulation of apoptotic genes, and inhibition of cell proliferation and angiogenesis in cancer cells. In this review, we discuss about the anticancer profile of luteolin.

Benzimidazole-carbamate anthelmintics: Perspective candidates for the anticancer drug development.

Cellular oncogenesis involves a complex interplay between the several synchronized, interdependent pathways that collectively determine the pathogenesis and pathophysiology of cancer. Limited therapeutic success with the existing anticancer drugs drew huge interest in the design and development of new pharmacophores with improved clinical efficacy, however despite huge investments in anticancer RD; the average number of Food and Drug Administration-approved anticancer drugs declined since the 1990s. The contemporary anticancer medications possess high attrition rates, bear substantial costs, and experience low efficacy owing to the drug resistance expressed by the aggressive tumors. Mainly, the translation of novel candidate anticancer drugs into clinical practice, their commercialization, and transformation from the bench to bedside require a long timeframe of 10-15 years and capital worth millions of dollars. The repurposing strategy substantially accelerated the anticancer drug development regime as the approved drugs with tested safety and efficacy ensure a minimal risk of failure, and nominal R&D expenses as anticipated for the newly identified candidate drugs yet to enter the clinical trials. In addition, the repurposed drugs ensure a rapid clinical translation due to a validated clinical profile and their ability to target the identified hallmarks and hitherto unknown vulnerabilities of cancer. The flagship project "Repurposing Drugs in Oncology" (ReDO) identified 268 "hard repurposing" noncancer medications as candidate drugs with a promising anticancer profile (https://www.anticancerfund.org/en/redo-db). However, the generic profile of 84% of repurposed drugs in ReDO data set discourages the commercial sponsors from funding the repurposing trials, especially the Phase III efficacy trials that require significant capital.

Medicinal chemistry of pyrophosphate mimics: A mini review.

The pyrophosphate mimicking groups offer rational modification of the pyrophosphate-bearing natural substrates of the overexpressed enzymes that cause the onset of disease progression. Mainly, the modified substrate interacts differently with the enzyme active site eventually causing its deactivation, or provides the therapeutically active products at the completion of the catalytic cycle that contribute toward the inhibition of the target enzyme. Many of the pyrophosphate mimic-containing molecules serve as competitive or allosteric inhibitors of the target enzyme to achieve the desirable properties for the mitigation of the target enzyme's pathophysiology. This review presents an epigrammatic overview of the pyrophosphate mimics in medicinal chemistry.

Medicinal chemistry of anthranilic acid derivatives: A mini review.

Anthranilic acid and its analogues present a privileged profile as pharmacophores for the rational development of pharmaceuticals deliberated for managing the pathophysiology and pathogenesis of various diseases. The substitution on anthranilic acid scaffold provides large compound libraries, which enable a comprehensive assessment of the structure activity relationship (SAR) analysis for the identification of hits and leads in a typical drug development paradigm. Besides, their widespread applications as anti-inflammatory fenamates, the amide and anilide derivatives of anthranilic acid analogues play a central role in the management of several metabolic disorders. In addition, these derivatives of anthranilic acid exhibit interesting antimicrobial, antiviral and insecticidal properties, whereas the derivatives based on anthranilic diamide scaffold present applications as P-glycoprotein inhibitors for managing the drug resistance in cancer cells. In addition, the anthranilic acid derivatives serve as the inducers of apoptosis, inhibitors of hedgehog signaling pathway, inhibitors of mitogen activated protein kinase pathway, and the inhibitors of aldo-keto reductase enzymes. The antiviral derivatives of anthranilic acid focus on the inhibition of hepatitis C virus NS5B polymerase to manifest considerable antiviral properties. The anthranilic acid derivatives reportedly present neuroprotective applications by downregulating the key pathways responsible for the manifestation of neuropathological features and neurodegeneration. Nevertheless, the transition metal complexes of anthranilic acid derivatives offer therapeutic applications in diabetes mellitus, and obesity by regulating the activity of α-glucosidase. The present review demonstrates a critical analysis of the therapeutic profile of the key derivatives of anthranilic acid and its analogues for the rational development of pharmaceuticals and therapeutic molecules.

"Azole" as privileged heterocycle for targeting the inducible cyclooxygenase enzyme.

An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.

Targeting cyclooxygenase enzyme for the adjuvant COVID-19 therapy.

Despite vigorous efforts, the COVID-19 pandemic continues to take a toll on the global health. The contemporary therapeutic regime focused on the viral spike proteins, viral 3CL protease enzyme, immunomodulation, inhibition of viral replication, and providing a symptomatic relief encouraged the repurposing of drugs to meet the urgency of treatment. Similarly, the representative drugs that proved beneficial to alleviate SARS-CoV-1, MERS-CoV, HIV, ZIKV, H1N1, and malarial infection in the past presented a sturdy candidature for ameliorating the COVID-19 therapeutic doctrine. However, most of the deliberations for developing effective pharmaceuticals proved inconsequential, thereby encouraging the identification of new pathways, and novel pharmaceuticals for capping the COVID-19 infection. The COVID-19 contagion encompasses a burst release of the cytokines that increase the severity of the infection mainly due to heightened immunopathogenicity. The pro-inflammatory metabolites, COX-2, cPLA2, and 5-LOX enzymes involved in their generation, and the substrates that instigate the origination of the innate inflammatory response therefore play an important role in intensifying and worsening of the tissue morbidity related to the coronavirus infection. The deployment of representative drugs for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Aspirin, Indomethacin, Diclofenac, and Celecoxib in COVID-19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs respectively, have provided a silver lining in adjuvant COVID-19 therapy. Since the anti-inflammatory NSAIDs and COXIBs mainly function by reversing the COX-2 overexpression to modulate the overproduction of pro-inflammatory cytokines and chemokines, these drugs present a robust treatment option for COVID-19 infection. This commentary succinctly highlights the various claims that support the status of immunomodulatory NSAIDs, and COXIBs in the adjuvant COVID-19 therapy.

Therapeutic delivery with V-amylose.

The helical structure of V-amylose offering a superior encapsulation affinity compared with the other polysaccharides, especially toward the amphiphilic or hydrophobic molecules; in addition to providing a higher resistance toward enzymatic hydrolysis support its applications as a potential drug delivery vehicle. Mainly, the glycosidic linkages and -CH2 - groups forming the hydrophobic cavity of V-amylose helix, and the glycosyl hydroxyl groups constituting its hydrophilic periphery promote the loading of a diverse range of molecules via van der Waals forces and hydrogen bonding interactions. These properties enable a high-loading efficiency, targeted delivery, and controlled release of the cargo drug molecules by V-amylose. Besides, V-amylose presents characteristics of an ideal drug delivery system, such as biocompatibility, physiological benevolence, nonimmunogenicity, and biodegradability. The V-amylose polysaccharide chains fold into left-handed single helix comprising of six glucose units in each turn having a pitch height of 7.91-8.17 Å. These structural features of V-amylose differentiate it from the parent amylose polysaccharide and enable the accommodation and nanoencapsulation of a wide range of therapeutics in the former. The tightly packed helical structure of V-amylose provides extraordinary resistance toward digestion by amylase compared with the linear polysaccharides, which supports the application of V-amylose as controlled drug release systems. The activity of the amylase enzyme produced by salivary glands, pancreas, gastrointestinal tract, and gut microbiota on amylose-based drug delivery vehicles promote enzyme-sensitive controlled oral and colon-specific release of the encapsulated drug. The single helical V-amylose with hydrophobic core and hydrophilic periphery forms inclusion complexes that improve the absorption and permeation of drugs having a high clogP index. The present commentary highlights the distinguished features of V-amylose as an imminent drug delivery system.

Drug encapsulating polysaccharide-loaded metal nanoparticles: A perspective drug delivery system.

The anticancer and antimicrobial drugs customarily suffer a functional inefficacy due to a limited delivery to the target site, active cellular efflux, in addition to the inadequacy of carrier system. Metal nanoparticles possess unique physicochemical properties as drug delivery vehicles, for delivering the drugs susceptible to cellular efflux pumps. However, a direct physiological exposure of nanoparticle surface after releasing the carrier drug poses serious concerns. The polysaccharides with enhanced biotolerance used for encapsulating the cargo drug molecules, when loaded on the nanoparticle surface presents a perspective drug delivery system combining the physiological benevolence of the former and theranostic/efflux pump evading features of the latter. The present commentary highlight the importance of metal nanoparticle-loaded polysaccharides as perspective drug delivery system.

Barbiturate derivatives for managing multifaceted oncogenic pathways: A mini review.

Development and progression of metastasis comprises synchronized erroneous expressions of several composite pathways, which are difficult to manage simultaneously with the representative anticancer molecules. The emergence of the drug resistance and the complex interplay between these pathways further potentiates cancer related complexities. Barbiturates and their derivatives present a commendable anticancer profile by attenuating the cancer manifesting metabolic and enzymatic pathways including, but not limited to matrix metalloproteinases, xanthine oxidase, amino peptidases, histone deacetylases, and Ras/mitogen-activated protein kinase. The derivatization and conjugation of barbiturates with pharmacophores delivers a suitable hybrid profile in containing the anomalous expression of these pathways. The present report presents a succinct collation of the barbiturates and their derivatives in managing the various cancer causing pathways.

Are Medicinal Plants an Alternative Strategy to Combat COVID-19?

No Abstract Available.

Letter to the Editor: Integrating the Roles of Pharmacy Practice and Drug Delivery in Mitigating COVID-19.

No Abstract Available.

Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review.

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.

Synthesis and evaluation of amylose-mefenamic acid conjugates as colon-targeting prodrugs.

Aim: Amide-linked amylose-based prodrugs were developed for colon-targeted release of mefenamic acid. Materials & methods: Activation of prodrug was studied spectrophotometrically, enzyme-linked immunosorbent assay appraised cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition at different concentrations of the prodrug, the behavior of prodrug under physiological conditions was monitored by scanning electron microscopy. Results: Prodrug was poorly activated in the enzyme-free simulated gastric media and simulated intestinal media (SIM) but preincubation in pancreatin followed by treatment in aminopeptidase containing SIM led to a significant activation of prodrug. Conclusion: Amide-linked amylose-mefenamic acid conjugates showed a slow release in simulated gastric media and a controlled release in SIM with pancreatin playing an important role in drug release.

The contemplation of amylose for the delivery of ulcerogenic nonsteroidal anti-inflammatory drugs.

This manuscript proposes an innovative approach to mitigate the gastrointestinal adversities linked with nonsteroidal anti-inflammatory drugs (NSAIDs) by exploiting amylose as a novel drug delivery carrier. The intrinsic attributes of V-amylose, such as its structural uniqueness, biocompatibility and biodegradability, as well as its capacity to form inclusion complexes with diverse drug molecules, are meticulously explored. Through a comprehensive physicochemical analysis of V-amylose and ulcerogenic NSAIDs, the plausibility of amylose as a protective carrier for ulcerogenic NSAIDs to gastrointestinal regions is elucidated. This review further discusses the potential therapeutic advantages of amylose-based drug delivery systems in the management of gastric ulcers. By providing controlled release kinetics and enhanced bioavailability, these systems offer promising prospects for the development of more effective ulcer therapies.