1,2,3-Triazolyl-tetrahydropyrimidine Conjugates as Potential Sterol Carrier Protein-2 Inhibitors: Larvicidal Activity against the Malaria Vector Anopheles arabiensis and In Silico Molecular Docking Study.

Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure-activity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules' potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.

Thiazole: A Versatile Standalone Moiety Contributing to the Development of Various Drugs and Biologically Active Agents.

For many decades, the thiazole moiety has been an important heterocycle in the world of chemistry. The thiazole ring consists of sulfur and nitrogen in such a fashion that the pi (π) electrons are free to move from one bond to other bonds rendering aromatic ring properties. On account of its aromaticity, the ring has many reactive positions where donor-acceptor, nucleophilic, oxidation reactions, etc., may take place. Molecules containing a thiazole ring, when entering physiological systems, behave unpredictably and reset the system differently. These molecules may activate/stop the biochemical pathways and enzymes or stimulate/block the receptors in the biological systems. Therefore, medicinal chemists have been focusing their efforts on thiazole-bearing compounds in order to develop novel therapeutic agents for a variety of pathological conditions. This review attempts to inform the readers on three major classes of thiazole-bearing molecules: Thiazoles as treatment drugs, thiazoles in clinical trials, and thiazoles in preclinical and developmental stages. A compilation of preclinical and developmental thiazole-bearing molecules is presented, focusing on their brief synthetic description and preclinical studies relating to structure-based activity analysis. The authors expect that the current review may succeed in drawing the attention of medicinal chemists to finding new leads, which may later be translated into new drugs.

Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines.

Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC-3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis.

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (3a-3i) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively.To understand the mechanism of action of these compounds (3a-3i) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a, promising leads worthy of further optimisation.

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme.

A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives.

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a-e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, ß = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

Synthesis and evaluation of 2,4,5-trisubstitutedthiazoles as carbonic anhydrase-III inhibitors.

A series of 17 compounds (12-16 b) with 2,4,5-trisubstitutedthiazole scaffold having 5-aryl group, 4-carboxylic acid/ester moiety, and 2-amino/amido/ureido functional groups were synthesised, characterised, and evaluated for their carbonic anhydrase (CA)-III inhibitory activities using the size exclusion Hummel-Dreyer method (HDM) of chromatography. Compound 12a with a free amino group at the 2-position, carboxylic acid moiety at the 4-position, and a phenyl ring at the 5-position of the scaffold was found to be the most potent CA-III inhibitor (Ki = 0.5 µM). The presence of a carboxylic acid group at the 4-position of the scaffold was found to be crucial for the CA-III inhibitory activity. Furthermore, replacement of the free amino group with an amide and urea group resulted in a significant reduction of activity (compounds 13c and 14c, Ki = 174.1 and 186.2 µM, respectively). Thus, compound 12a (2-amino-5-phenylthiazole-4-carboxylic acid) can be considered as the lead molecule for further modification and development of more potent CA-III inhibitors.

Molecular signaling of G-protein-coupled receptor in chronic heart failure and associated complications.

The well-known condition of heart failure is a clinical syndrome that results when the myocardium's ability to pump enough blood to meet the body's metabolic needs is impaired. Most of the cardiac activity is maintained by adrenoceptors, are categorized into two main α and ß and three distinct subtypes of ß receptor: ß1-, ß2-, and ß3-adrenoceptors. The ß adrenoreceptor is the main regulatory macro proteins, predominantly available on heart and responsible for down regulatory cardiac signaling. Moreover, the pathological involvement of Angiotensin-converting enzyme 1 (ACE1)/angiotensin II (Ang II)/angiotensin II type 1 (AT1) axis and beneficial ACE2/Ang (1-7)/Mas receptor axis also shows protective role via Gi ßγ, during heart failure these receptors get desensitized or internalized due to increase in the activity of G-protein-coupled receptor kinase 2 (GRK2) and GRK5, responsible for phosphorylation of G-protein-mediated down regulatory signaling. Here, we investigate the various clinical and preclinical data that exhibit the molecular mechanism of upset level of GRK change the cardiac activity during failing heart.

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation.

Malaria, affecting all continents, remains one of the life-threatening diseases introduced by parasites that are transmitted to humans through the bites of infected Anopheles mosquitoes. Although insecticides are currently used to reduce malaria transmission, their safety concern for living systems, as well as the environment, is a growing problem. Therefore, the discovery of novel, less toxic, and environmentally safe molecules to effectively combat the control of these vectors is in high demand. In order to identify new potential larvicidal agents, a series of 2-aryl-1,2-dihydroquinazolin-4-one derivatives were synthesized and evaluated for their larvicidal activity against Anopheles arabiensis. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compounds were also investigated and most of the derivatives possessed a favorable ADMET profile. Computational modeling studies of the title compounds demonstrated a favorable binding interaction against the acetylcholinesterase enzyme molecular target. Thus, 2-aryl-1,2-dihydroquinazolin-4-ones were identified as a novel class of Anopheles arabiensis insecticides which can be used as lead molecules for the further development of more potent and safer larvicidal agents for treating malaria.

Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches.

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation.Communicated by Ramaswamy H. Sarma.

Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies.

In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 µg/mL and 16-64 µg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 µg/mL and 16 µg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10-52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition. Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which ß-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Icacinaceae Plant Family: A Recapitulation of the Ethnobotanical, Phytochemical, Pharmacological, and Biotechnological Aspects.

Icacinaceae, an Angiospermic family comprising 35 genera and 212 accepted species, including trees, shrubs, and lianas with pantropical distribution, is one of the most outshining yet least explored plant families, which despite its vital role as a source of pharmaceuticals and nutraceuticals has received a meagre amount of attraction from the scientific community. Interestingly, Icacinaceae is considered a potential alternative resource for camptothecin and its derivatives, which are used in treating ovarian and metastatic colorectal cancer. However, the concept of this family has been revised many times, but further recognition is still needed. The prime objective of this review is to compile the available information on this family in order to popularize it in the scientific community and the general population and promote extensive exploration of these taxa. The phytochemical preparations or isolated compounds from the Icacinaceae family have been centrally amalgamated to draw diverse future prospects from this inclusive plant species. The ethnopharmacological activities and the associated endophytes and cell culture techniques are also depicted. Nevertheless, the methodical evaluation of the Icacinaceae family is the only means to preserve and corroborate the folkloristic remedial effects and provide scientific recognition of its potencies before they are lost under the blanket of modernization.

Mass spectrometry-based metabolomics approach and in vitro assays revealed promising role of 2,3-dihydroquinazolin-4(1H)-one derivatives against colorectal cancer cell lines.

Colorectal cancer (CRC) is the most frequent form of gastrointestinal cancer and one of the major causes of human mortality worldwide. Many of the current CRC therapies have limitations due to multidrug resistance and/or severe side effects. Quinazoline derivatives are promising lead compounds with a wide range of pharmacological actions. In this study, the effect of seven synthesized 2,3-dihydroquinazolin-4(1H)-one analogues as potential anticancer agents against two CRC cell lines (HCT116 and SW480) was investigated using cell viability proliferation, migration, adhesion and invasion assays. A liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics approach was used to identify the underlying biochemical pathways disturbed in treated-HCT116 cells. Cell viability proliferation assay revealed that four compounds (C2, C3, C5, and C7) had IC50 < 10 µM with C5 displaying the most potent cytotoxic effect (IC50 1.4 and 0.3 µM against HCT116 and SW480, respectively). Additionally, the compounds showed suppression of wound closure after 72 h, and both C2 and C5 significantly decreased the number of adherent cells and suppressed HCT116 cells invasion. Metabolomics study revealed that C5 induced significant perturbations in the level of several metabolites including spermine, polyamines, glutamine, creatine and carnitine, and altered biochemical processes essential for cell proliferation and progression such as amino acids biosynthesis and metabolism, redox homeostasis, energy related processes (e.g., fatty acid oxidation, second Warburg like effect) and one-carbon metabolism. Our findings indicate that 2,3-dihydroquinazolin-4(1H)-one analogues, particularly C5, have promising anticancer properties, and shed light on the role of metabolomics in identifying new therapeutic targets and providing better understanding of the pathways altered in treated cancer cells.

Synthesis, biological evaluation, and computational investigation of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates as potential larvicidal agents against Anopheles arabiensis.

Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.

Recent approaches in the drug research and development of novel antimalarial drugs with new targets.

Malaria is a serious worldwide medical issue that results in substantial annual death and morbidity. The availability of treatment alternatives is limited, and the rise of resistant parasite types has posed a significant challenge to malaria treatment. To prevent a public health disaster, novel antimalarial agents with single-dosage therapies, extensive curative capability, and new mechanisms are urgently needed. There are several approaches to developing antimalarial drugs, ranging from alterations of current drugs to the creation of new compounds with specific targeting abilities. The availability of multiple genomic techniques, as well as recent advancements in parasite biology, provides a varied collection of possible targets for the development of novel treatments. A number of promising pharmacological interference targets have been uncovered in modern times. As a result, our review concentrates on the most current scientific and technical progress in the innovation of new antimalarial medications. The protein kinases, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, isoprenoid biosynthesis inhibitors, and enzymes involved in the metabolism of lipids and replication of deoxyribonucleic acid, are among the most fascinating antimalarial target proteins presently being investigated. The new cellular targets and drugs which can inhibit malaria and their development techniques are summarised in this study.

Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors.

The reversible inhibition of acetylcholinesterase (AChE) has become a promising target for the treatment of Alzheimer's disease (AD) which is mainly associated with low in vivo levels of acetylcholine (ACh). The availability of AChE crystal structures with and without a ligand triggered the effort to find a structure-based design of acetylcholinesterase inhibitors (AChEIs) for AD. The major problem observed with the structure-based design was the feeble robustness of the scoring functions toward the correlation of docking scores with inhibitory potencies of known ligands. This prompted us to develop new prediction models using the stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LigandFit, and GLIDE). In the present investigation, a dataset of 91 molecules belonging to 9 different structural classes of heterocyclic compounds with an activity range of 0.008 to 281,000 nM was considered for docking studies and development of AChE-specific 3D-QSAR models. The model (M1) developed using consensus of docking scores of scoring functions viz. Glide score, Gold score, Chem score, ASP score, PMF score, and DOCK score was found to be the best (R(2) = 0.938, Q(2) = 0.925, R(pred)(2) = 0.919, R(2)m((overall)) = 0.936) compared to other consensus models. Docking studies revealed that the molecules with proper alignment in the active site gorge and the ability to interact with all the crucial amino acid residues, in particular by forming π-π stacking interactions with Trp84 at the catalytic anionic site (CAS) and Trp279 at peripheral anionic site (PAS), showed augmented potencies with consequent improvement in patient cognition and reduced the formation of senile plaques associated with AD. Further, the descriptors that signify the association of the ligands with the receptor as well as ADME properties of the ligands were also analyzed by means of the set of ligands that have been pre-positioned with respect to a receptor after docking analysis and considered as independent variables to generate a linear model (M3 and M4) using a stepwise multiple linear regression method to get additional insight into the physicochemical requirements for effective binding of ligands with AChE as well as for prediction of AChE inhibition. The developed AChE-specific prediction models (M1-M4) satisfactorily reflect the structure-activity relationship of the existing AChEIs and have all the potential to facilitate the process of design and development of new potent AChEIs.

Three-Dimensional In Vitro Cell Culture Models for Efficient Drug Discovery: Progress So Far and Future Prospects.

Despite tremendous advancements in technologies and resources, drug discovery still remains a tedious and expensive process. Though most cells are cultured using 2D monolayer cultures, due to lack of specificity, biochemical incompatibility, and cell-to-cell/matrix communications, they often lag behind in the race of modern drug discovery. There exists compelling evidence that 3D cell culture models are quite promising and advantageous in mimicking in vivo conditions. It is anticipated that these 3D cell culture methods will bridge the translation of data from 2D cell culture to animal models. Although 3D technologies have been adopted widely these days, they still have certain challenges associated with them, such as the maintenance of a micro-tissue environment similar to in vivo models and a lack of reproducibility. However, newer 3D cell culture models are able to bypass these issues to a maximum extent. This review summarizes the basic principles of 3D cell culture approaches and emphasizes different 3D techniques such as hydrogels, spheroids, microfluidic devices, organoids, and 3D bioprinting methods. Besides the progress made so far in 3D cell culture systems, the article emphasizes the various challenges associated with these models and their potential role in drug repositioning, including perspectives from the COVID-19 pandemic.

Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing.

The introduction of selective COX-2 inhibitors (so-called 'coxibs') has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs 'controversial me-too' saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer's disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed.

Novel Therapies for the Treatment of Neuropathic Pain: Potential and Pitfalls.

Neuropathic pain affects more than one million people across the globe. The quality of life of people suffering from neuropathic pain has been considerably declining due to the unavailability of appropriate therapeutics. Currently, available treatment options can only treat patients symptomatically, but they are associated with severe adverse side effects and the development of tolerance over prolonged use. In the past decade, researchers were able to gain a better understanding of the mechanisms involved in neuropathic pain; thus, continuous efforts are evident, aiming to develop novel interventions with better efficacy instead of symptomatic treatment. The current review discusses the latest interventional strategies used in the treatment and management of neuropathic pain. This review also provides insights into the present scenario of pain research, particularly various interventional techniques such as spinal cord stimulation, steroid injection, neural blockade, transcranial/epidural stimulation, deep brain stimulation, percutaneous electrical nerve stimulation, neuroablative procedures, opto/chemogenetics, gene therapy, etc. In a nutshell, most of the above techniques are at preclinical stage and facing difficulty in translation to clinical studies due to the non-availability of appropriate methodologies. Therefore, continuing research on these interventional strategies may help in the development of promising novel therapies that can improve the quality of life of patients suffering from neuropathic pain.

Environmental sustainable mathematically processed UV spectroscopic methods for quality control analysis of remogliflozin and teneligliptin: Evaluation of greenness and whiteness.

Environmental sustainable analytical methods were developed by mathematical modification of UV absorption spectra for quality control study of multicomponent formulations consisting of remogliflozin (REM) and teneligliptin (TEN), with good sensitivity and selectivity. Then analytes were quantified by measuring the peak amplitude of the first derivative spectra at zero crossing points at 230.2 nm and 213.8 nm for REG and TEN in the first derivative method. The second method involves the formation of ratio spectra and taking the absorption difference at two selected wavelengths of peak and trough of a spectrum. In the ratio first derivative method peak amplitudes were measured at 235.2 nm and 259.1 nm for simultaneous quantification of REM and TEN respectively. The fourth method was based on the measurement of the peak amplitude of zero-order spectra of analytes generated from the mixture spectrum by subtraction of a constant from the ratio spectrum followed by multiplication with divisor spectrum, Further, the proposed methods were validated systematically to confirm the linearity, precession, accuracy, sensitivity, and selectivity. Finally, validated UV spectroscopic methods were applied for simultaneous quantification of REM and TEN from formulation, and laboratory mixed solutions and statistically compared with the reported HPLC method. Further, recently developed AGREE, Hexagonal greenness and white analytical chemistry, a whiteness evaluation tools were applied to the proposed UV spectroscopic methods and found to be safer analytical methods, compared to the reported expensive, time-consuming and toxic HPLC method. Hence, proposed UV spectroscopic methods could be used for routine quality control of formulations containing REM and TEN.