Strategies in synthetic design and structure-activity relationship studies of novel heterocyclic scaffolds as aldose reductase-2 inhibitors.

Heterocyclic scaffolds of natural as well as synthetic origin provide almost all categories of drugs exhibiting a wide range of pharmacological activities, such as antibiotics, antidiabetic and anticancer agents, and so on. Under normal homeostasis, aldose reductase 2 (ALR2) regulates vital metabolic functions; however, in pathological conditions like diabetes, ALR2 is unable to function and leads to secondary diabetic complications. ALR2 inhibitors are a novel target for the treatment of retinopathy (cataract) influenced by diabetes. Epalrestat (stat), an ALR2 inhibitor, is the only drug candidate that was approved in the last four decades; the other drugs from the stat class were retracted after clinical trial studies due to untoward iatrogenic effects. The present study summarizes the recent development (2014 and onwards) of this pharmacologically active ALR2 heterocyclic scaffold and illustrates the rationale behind the design, structure-activity relationships, and biological studies performed on these molecules. The aim of the current review is to pave a straight path for medicinal chemists and chemical biologists, and, in general, to the drug discovery scientists to facilitate the synthesis and development of novel ALR2 inhibitors that may serve as lead molecules for the treatment of diseases related to the ALR2 enzyme.

Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors.

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 µM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 µM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

An appraisal of anticancer activity with structure-activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review.

Cancer is one of the leading causes of death. Globally a huge number of deaths and new incidences are reported annually. Heterocyclic compounds have been proved to be very effective in the treatment of different types of cancer. Among different heterocyclic scaffolds, quinazoline and quinazolinone core were found versatile and interesting with many biological activities. In the discovery of novel anticancer agents, the Quinazoline core is very effective. The FDA has approved more than 20 drugs as an anticancer bearing quinazoline or quinazolinone core in the last two decades. One prime example is Dacomitinib, which was newly approved for non-small-cell lung carcinoma treatment in 2018. These drugs work by different pathways to prevent the spread of cancer cell progression, including inhibition of different kinases, tubulin, kinesin spindle protein, and so forth. This review presented recent developments of quinazoline/quinazolinone scaffold bearing derivatives as anticancer agents acting as epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR), and dual EGFR/VEGFR inhibitors.

Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

Pharmacophore based drug design and synthesis of oxindole bearing hybrid as anticancer agents.

Dual TK inhibitors have shown significant clinical effects against many tumors, but with unmanageable side effects. Design approach and selectivity of these inhibitors plays substantial role in their potency and side-effects. Understanding the homology of binding sites in targeted receptors, and involvement of signaling proteins after the inhibition might help in producing less toxic but effective inhibitors. Herein, we designed benzylideneindolon-2-one derivatives based on homology modeling in binding sites of VEGFR-2 and EGFR receptors as dual- inhibitor potent anticancer compounds with high selectivity. The benzylideneindolon-2-one derivatives were found to possess conformational switch in form of oxindole, substituted at 2-benzimidazole. Within synthesized compounds, 5b was found most active in in-vitro enzyme inhibition assay against VEGFR-2 and EGFR with highest IC50 value of 6.81 ± 2.55 and 13.04 ± 4.07 nM, respectively. Interestingly, cytotoxicity studies revealed selective toxicity of compound 5b against proliferation of A-431 cell lines (over expressed VEGFR-2 and EGFR) with GI50 value of 0.9 ± 0.66 µM. However, the compounds showed mild to moderate activity in all other cancer cell line in the range of 0.2-100 µM. Further mode of action studies by flow cytometry and western blot on A-431 indicated that they work via apoptosis at S- phase following Bcl/Bax pathway, and cell migration via MMP9. 5b not only suppressed tumor growth but also improved vandetanib associated with weight loss toxicity. Moreover, 5b was found safer than sunitinib and erlotinib with LD50 of 500 mg/kg body weight. These results propose 5b as potential anti-tumor drug with safer profile of conventional inhibitors of VEGFR-2 and EGFR for solid tumors.

Advances in 2-substituted benzothiazole scaffold-based chemotherapeutic agents.

Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential. Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents.

Aromatase inhibitors: Role in postmenopausal breast cancer.

Postmenopausal women are at high risk of developing breast cancer due to estrogen production in peripheral tissues of the body other than ovaries. Aromatase is present in breast tissue, leading to local estrogen production which can be inhibited by a variety of steroidal and nonsteroidal aromatase inhibitors. There are many aromatase inhibitors available in clinical practice like exemestane, formestane, anastrozole, letrozole, fadrozole, vorozole, and so forth, but the major challenge in anti-breast cancer therapy is the toxicity associated with aromatase inhibitors, especially the steroidal class of drugs. It is, therefore, urgently required to develop novel anticancer drugs having better safety and efficacy for the treatment of breast cancer. This study highlights the aromatase inhibitors reported in the current literature as well as the recent advances in the management of breast cancer.

Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review.

Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase-4 (DPP-4) inhibition is an exciting and new approach in the treatment of type-2 diabetes. DPP-4 inhibitors or "gliptins" are weight neutral, pose lesser risk of hypoglycemia, and provide a long-term post-meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti-diabetic drugs.

Formulation and development of novel lipid-based combinatorial advanced nanoformulation for effective treatment of non-melanoma skin cancer.

Non-melanoma skin cancer is one of the most common malignancies reported with high number of morbidities, demanding an advanced treatment option with superior chemotherapeutic effects. Due to high degree of drug resistance, conventional therapy fails to meet the desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The NLCs were optimized using central composite design that showed an average particle size of 206 nm and a zeta potential of -34 mV. In addition, in vitro and ex vivo drug permeations studies demonstrated the effective delivery of both drugs in the skin layers via lipid structured nanocarriers. Also, the prepared FU-CBD-NLCs showed promising effect in-vitro cell studies including MTT assays, wound healing and cell cycle as compared to the conventional formulation. Moreover, dermatokinetic studies shows there was superior deposition of drugs at epidermal and the dermal layer when treated with FU-CBD-NLCs. In the end, overall study offered a novel combinatorial chemotherapy that could be an option for the treatment of non-melanoma skin cancer.

Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design.

INTRODUCTION: Hyperactivated RAS signaling is reported in 13% of all human cancers, in which ~80% resulted due to KRAS mutations alone. Direct inhibition of KRAS is an important aspect in treating KRAS-related tumors. Despite the efforts of more than four decades, not many KRAS inhibitors have been successful in obtaining clinical approval, except the very recent FDA approval for sotorasib. In recent years, the understanding of structural insights and allosteric pocket identification at catalytic sites of KRAS are likely to provide an excellent opportunity for the development of much more effective clinical candidates. AREA COVERED: The presented review article mainly summarizes the developments of small molecule KRAS inhibitors as drug candidates and rational approaches that are being utilized for the selective targeting of KRAS signaling in the mutant cancer cells. EXPERT OPINION: After the initial success in targeting the mutant KRAS G12C variants, the search has been shifted to address the challenges concerning the resistance and efficacy of small molecule KRAS inhibitors. However, the contribution of other KRAS mutations at G12V, G13C, and G13D variants causing cancers is much higher than the mutations at G12C. In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.

Role of colchicine in the management of COVID-19 patients: A meta-analysis of cohort and randomized controlled trials.

Background: Colchicine is well known drug for the treatment of acute gout. Recently, it has also been used in the management of COVID-19 patients. Aim: The aim of current study is to find out the role of colchicine in COVID-19 patients. Material & methods: The relevant studies were searched in PubMed/Medline, Google scholar and clinical trail.gov.com till inception and sorted based on the inclusion and exclusion criteria. The quality assessment of studies were done using Newcastle Ottawa Quality Assessment Scale. The pooled estimate was calculated as odd ratio and pooled prevalence with 95% confidence interval. A random effect model was used and publication bias was assessed qualitatively by trim and fill method. Results: Out of 38 studies, a total of 6 studies were found relevant for the analysis containing 1146 patients (705 males and 441 females). The pooled odd ratio was found to be 0.35 [0.23, 0.53] which indicate significance reduction of mortality in colchicine group as compared to non-colchicine group. The pooled prevalence of the patients treated with colchicine were found to be significant [0.11(0.03, 0.24)]. The heterogeneity among studies was also found to be low (I2 = 11%). However, funnel plot has indicated the involvement of publication bias [Egger: bias = 10.168291 (95% CI = 5.042044 to 15.294537) P = 0.0053]. Conclusion: Colchicine might be helpful in reduction of mortality in the management of COVID-19 patients. However, further studies are required to confirm its exact role.

Free radical scavengers: An overview on heterocyclic advances and medicinal prospects.

In the present scenario, there has been a lot of consideration toward the field of free radical chemistry. Free radicals responsive oxygen species are produced by different endogenous frameworks, exposure to various physicochemical conditions, radiation, toxins, metabolized drug by-product, and pathological states. On the off chance that free radical overpowers the body's capacity, it generates a condition known as oxidative stress, which can alter physiological conditions of the body and results in several diseases. For appropriate physiological function, it is necessary to have a proper balance between free radicals and antioxidants. Antioxidants chemically inhibit the oxidation process; they are also known as free radical scavengers. For tackling the problem of oxidative stress application of an external source of antioxidant is helpful. A lot of antioxidants of natural, semi-synthetic and synthetic origin are in use, with time search of more effective, nontoxic, safe antioxidant is intensified. The present review, discuss different synthetic derivatives bearing various heterocyclic scaffolds as radical scavengers.

Synthetic lethality on drug discovery: an update on cancer therapy.

INTRODUCTION: A novel anticancer therapy is the need of the hour due to growing incidences of resistance to first line cancer chemotherapy. Synthetic lethality (SL) is one of the new age treatment methods being explored for combating the resistance to anticancer agents. In this method, cell mutations are exploited for the development of new therapeutic agents, where, if there is loss of function of one gene, the cell mutations can still be fixed by alternative machinery but if two genes involved in DNA repair undergo loss of function, it causes lethality to the cell. AREAS COVERED: The authors condense findings of SL-based novel anticancer regimen. The review emphasizes some of the SL based clinical and preclinical studies of novel targets and therapy. EXPERT OPINION: SL conceptualizes a resolution against treatment resistance to anticancer regimen by recognition of therapeutic vulnerabilities in particular cancer cells. A multitude of clinical trials associated with SL and DNA repair are being conducted that will be useful in obtaining a clearer picture pertaining to the use of cancer biomarkers and effectiveness of drugs acting via target-based molecular changes. Furthermore, new anticancer regimen focused on personalized medicines will emerge basing their development upon SL.

Tubulin inhibitors as novel anticancer agents: an overview on patents (2013-2018).

Introduction: About 20 patents have been published from 2013 to 2018 for developing advanced cancer therapeutics by targeting tubulin polymerization. Currently, there are several tubulin inhibitors that are in the drug development pipeline for various cancers alone or in combination including antibody-conjugated drugs (ACDs). Areas covered: Important patents focusing on the development of tubulin inhibitors published from 2013 to 2018 are covered. This review mainly focuses on the tubulin inhibitors that are being synthesized and studied in cancer research along with their structures and their phases of development in preclinical and clinical research. Expert opinion: Regulation of microtubules is important for cell division, cell motility, intracellular transport, and cell shape maintenance. Modulating its activity proved to be very effective in various diseases including different types of cancers. Microtubules are composed of two units, namely, alpha and beta-tubulin, and modifications at these ends affect both its functions and dynamics. A number of compounds that have been designed and synthesized bearing various heterocyclic scaffolds have been proven to modulate its activity and have emerged as potent tubulin inhibitors. This encourages more to study microtubules in order to find a variety of novel, potent compounds as anticancer drugs.

Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review.

Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.

DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective.

Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of ß-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aß 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.