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The third-generation EGFR (epidermal growth factor receptor) inhibitors selectively and irreversibly target EGFR-T790M and other activating EGFR mutations. Osimertinib is the only FDA-approved third-generation inhibitor, which has a good potency against the EGFR-T790M mutant with minimal toxicities and excellent selectivity for wild-type EGFR. EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after the treatment of osimertinib, which is an undruggable mutation to all three existing generation drugs. Recently, trisubstituted imidazoles were reported based on an off-target hit of a p38α MAPK (mitogen-activated protein kinase) inhibitor as the fourth-generation EGFR-TKIs to overcome the C797S resistance by inhibiting the clinically relevant triple mutant kinase L858R/T790M/C797 EGFR. Here, we are reporting the clinical trial p38α MAPK kinase inhibitors SD-06, Amgen 16, RWJ67657 and SCIO-323 as L858R/T790M/C797S EGFR TK inhibitors to overcome the problem of drug resistance in non-small cell lung cancer (NSCLC).Communicated by Ramaswamy H. Sarma.

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

Bedaquiline was approved by USFDA in 2012 for pulmonary MDR-TB. The IC50 value of bedaquiline was reported to be remarkably low (25 nM), effectively inhibiting mycobacterial ATP synthase. In addition to these obvious assets of bedaquiline, the potential disadvantages of bedaquiline include inhibition of the hERG (human Ether-a-go-related gene; KCNH2) potassium channel (concurrent risk of cardiac toxicity), hepatic toxicity and possibly phospholipidosis. The current review focuses primarily on the structural part of bedaquiline for the activity-toxicity optimization. This critical analysis of the structure of bedaquiline will help medicinal chemists to synthesize the better modified analouge of bedaquiline with reduced cardiotoxicity, hepatotoxicity potential and improved pharmacokinetics.

Tuberculosis is considered as a leading health issue globally. Even though, the todays first line anti-mycobacterial treatments used in the hospital have low deaths, multidrug-resistance forms of the ailment have now spread globally and become a major issue. The wide-ranging biodiversity of medicinal plants, ocean animals have gained considerable attention for drug discovery in previous spans, and the emergence of TB drug resistance has inspired interest in judging natural products (NPs) to cure this disease. Till now, several compounds have been isolated from natural sources with anti-mycobacterial activity, few of which demonstrate significant activity and have the potential for further development. Worldwide huge natural flora and fauna are existing, this flora and fauna must be investigated for new potent lead against infectious TB. This review systematically surveys various classes of terpenoid molecules obtained from different medicinal plants, fungi, sponges, and sea plumes with anti-TB activity, which could be useful for further optimization and development in this field.

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.

Background: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. Methods: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. Results: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. Conclusion: These compounds also showed less inclination towards WT-EGFR.

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. In this work, we have reported the novel T790M/C797S-EGFR Tyrosine Kinase inhibitors using BREED based de novo hybridization approach. BREED generates novel inhibitors from structures of known ligands bound to a common target. Among the generated hybridised breed compounds, the top best scorer breed molecules were breed 436, breed 530, breed 450, breed 562 and breed 313. Molecular Dynamics simulation of breed 436 for 10 ns further suggested that docked compound was stable into the pocket of the T790M/C797S-EGFR Tyrosine Kinase. In silico pharmacokinetic predictions of the breed hybridised compounds were within the defined range described for human use. Communicated by Ramaswamy H. Sarma

Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to delineate the design, synthesis, in vitro biological analysis of a series of novel reversible selective T790M inhibitors with minimal cardiotoxicity. Amongst the virtually sorted compounds; compound 18 and 74 have been located to be the foremost active compounds of the series with IC50 value of 0.88, 0.92 μM in cellular assay and 0.56, 0.62 μM in enzymatic assay, against double mutant L858R/T790M EGFR. Additionally, they showed much less affinity toward wild-type (WT)-EGFR with minimal cardiotoxicity.

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle. EGFR C797S mutation was accounted to be a main mechanism of resistance to the third-generation inhibitors. The C797S mutation gives off an impression of being an ideal target for conquering the acquired resistance to the third generation inhibitors. We have performed structure based-virtual screening strategies for binding of glucokinase activator to EGFR C797S, which can overcome EGFR resistance impediment with mutant-selective allosteric inhibition towards all kinds of mutant EGFR (T790M, L858R, TMLR) and WT EGFR. The final filter of Lipinski's Rule of Five, Jargan's Rule of Three and in silico ADME predictions gave 23 hits, which conform to Lipinski's rule and Jorgensen's rule and all their pharmacokinetic parameters are inside the appropriate range characterized for human use, in this manner demonstrating their potential as a drug-like molecule.

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.

Mycobacterium tuberculosis (MTB) infection has become an increasing health threat due to the worldwide emergence of multidrug-resistant MTB (MDR-MTB) strain. Isoniazid (pyridine) resistance problem is a complex process and is associated with mutations in several genes. However, the emergence of isoniazid (INH) resistant M. tuberculosis strains dictates the necessity for redesigning this old drug in order to create analogs effective against INH-resistant strains by using rational approach. In light of these findings, the present review discusses the synthesis, structural optimization, and modification in pyridine structure to combat the problem of multidrug-resistant tuberculosis.

The brain-blood ratio is an important model correlating the brain-targeting ability of neurotherapeutics with the CNS pharmacokinetics, which need to be presented before the scientific community for exploration of its scientific worth. The purpose of this article is to bring this key concept and its precise discussion to the attention of the researchers.Three major points are discussed herein: First, the significance of brain-blood ratio with respect to investigational neurotherapeutics, and carrier systems and correlation of its research findings with the brain targeting efficiency. Second, the various factors influencing the brain-blood ratio. Third, the various strategies for enhancing the brain-blood ratio. In addition, the benchmark criteria for CNS-likeness of drug molecules and the correlation of brain-blood ratio with brain targeting ability of neurotherapeutics have been tabulated.The brain-blood ratio (also referred to as the brain-plasma ratio) represents one of the tools available today for estimation of CNS pharmacokinetics. It is preferred over other complicated techniques (in situ brain perfusion and microdialysis) due to its ease of use and practicality. We are optimistic that the brain-blood ratio offers an excellent way of evaluating brain-targeting efficiency of neurotherapeutics effectively. In our opinion, it is a very fundamental aspect of brain bioavailability and needs to be presented in a precise way.

Throughout our evolution, the importance of natural products for medicine and health has been increasing and it continues to be a key source of novel anticancer drugs, leads and new chemical entities. Among natural products, tricyclic heteroaromatic alkaloids such as carbazoles are an important class of natural and semi-synthetic organic compounds. In the last few decades medicinal role of natural and semi-synthetic carbazoles has expanded significantly, especially as a vital heterocyclic class of antitumor agents. Some of the carbazoles that displayed potential anticancer activity have undergone clinical trials. However, complications arising due to multidrug resistance in clinical trials led to very few of the selected carbazoles being approved for cancer therapy. Planar, polycyclic and aromatic carbazoles exhibit anticancer activity via DNA intercalation. Further many carbazoles can be cytotoxic by inhibiting DNA-dependent enzymes such as telomerase and topoisomerase I/II.

There is an ever-increasing need for the development of new drugs with safe and improved profile for the treatment of cancer. From time immemorial, nature has been considered as an abundant source of medicinal compounds having therapeutic properties. An enormous chemical diversity is present in thousands and millions of species of microorganisms, marine organisms, plants and animals that can act as potential therapeutic agents against various types of human cancer. Literature survey revealed that many alkaloids isolated from marine cyanobacteria, fungi, algae, sponges and tunicates displayed a wide range of anticancer properties like antiproliferative, antiangiogenic, induction of apoptosis, promoting cytotoxicity by inhibition of topoisomerase activities and tubulin polymerization. In this context, bastadins derived from tyrosine-based alkaloids have been reported as one the important class of anticancer agents. In particular bastadin 6 (24), seems to be a promising natural lead compound for the development of marine natural product-based anticancer therapeutic agents. This review mainly highlights the pharmacologically active scaffolds like purine, tyrosine and tryptophan containing marine alkaloids that exhibit biological activity, including anti-angiogenesis, cytotoxicity and anticancer activity.

Overexpression of epidermal growth factor receptor (EGFR) is seen in a number of human tumors like prostate, colon, breast and ovarian. Their expression is correlated with vascularity and often difficult to diagnose. Though a number of active inhibitors and anticancer drugs against EGFR-tyrosine kinase are known, increase in resistance together with many side effects designate the need for new and improved treatments. Natural products and their analoges have significant contribution in the cancer drug discovery and development process. Therefore in the current review we mainly discuss design, synthesis and structural activity relationship of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors from the natural origin.

We herein report the synthesis and in vitro antimicrobial evaluation of twenty five novel hybrid derivatives of imidazo [2,1- b ]-1,3,4-thiadiazole containing chalcones ( 5a – o ) and Schiff bases ( 6a – j ) against three fungal strains ( Candida albicans , Cryptococcus neoformans and Aspergillus niger ). Most of the tested compounds displayed substantial anti-fungal activity with MICs ranging between 1.56 and 100 μg/mL. Compounds 5a , 5b and 5n exhibited promising activity against C. neoformans at a MIC 1.56 μg/mL. In addition, compound 5n also demonstrated significant antifungal activity against the clinical isolates of C. neoformans at MIC 3.125 μg/mL. However, moderate activity was observed for these compounds against four bacterial strains ( Staphylococcus aureus , Bacillus subtilis , Escherichia coli and Pseudomonas aeruginosa ) and Mycobacterium tuberculosis (H 37 Rv).

Troglitazone causes severe hepatic injury in certain individuals and multiple mechanisms related to hepato-toxicity has been reported creating confusion. In the present study, the mechanism for the hepatic injury of glitazones was investigated by PASS. The results suggest that chromane containing glitazones are apoptic agonist (activating p53 by intrinsic pathway leading to the apoptosis) and those which do not contain the chromane are devoid of this. In case of hepato-toxicity by non-chromane glitazone and their metabolite such as M-3, RM-3, rosiglitazone and pioglitazone; PASS suggest that these chemicals are not apoptic agonist but they are the substrate for CYP enzyme (Phase-I Oxidative Enzyme) and Phase-II conjugating enzymes; interfering with bile acid metabolism rendering bile acid more toxic (cholestasis). This unmetabolised bile salt further initiates the process apoptosis via intrinsic and extrinsic pathway leading to the apoptosis. Immunoblot analysis further confirm our hypothesis that troglitazone (chromane containing glitazone), but not rosiglitazone and pioglitazone (non-chromane containing glitazone) increased the levels of p53 in a time-dependent manner. Hence our prediction related to the mechanism of hepato-toxicity by apoptosis and structural insight of glitazone can be helpful in improving the drug profile of this category.

Aim and Objective: Kelch like ECH-associated protein 1 (Keap1) and Nuclear factor-E2 related factor 2 (Nrf2) binding is a key step in the ubiquitination and degradation of Nrf2. The compounds inhibiting this binding exert antioxidant actions. Naturally occurring pentacyclic triterpenoids (PTs) and their synthetic derivatives are projected as activators of Nrf2 signalling. The 16-mer Nrf2 peptide binding site on Keap-1 (PDB: 2 FLU) is proposed to be the prospective target where pentacyclic triterpenoid may exert protein-protein interaction. Material and Method: In the present study, seventy seven PTs of natural and synthetic origin are screened for Nrf2 stimulatory activity using online PASS (Prediction of Activity Spectrum of Substances) software followed by in silico molecular docking against 16-mer Nrf2 peptide binding site on Keap-1. This virtual screening reveals that Nrf2 stimulatory PTs dock on the 16-mer peptide binding site on Keap-1 and may exert their biological activities by interfering with the Keap-1 and Nrf2 binding. Results: In the present study shows that the small molecules like PT’s bind to keap 1 pocket where the 16 mer peptide of Neh2 domain of Nrf2. High docking score of -10.53, -9.08, -8.36, -7.94, -7.49 and -7.18 is shown by glycyrrhizin, asiatic acid, medecassic acid, barrigenic acid, rotundic acid, ursolic acid, respectively. Conclusion: The identified hits such as asiatic acid and medecassic acid represent a very promising starting point for the development of potent Nrf2 stimulator. The natural PTs are more promising than the most potent synthetic derivatives of oleanolic acid like CDDO, CDDO-methyl and CDDOimidazol.

The near future of drug delivery system would lie in the search of a versatile and innocuous material, based mostly on the natural resources. The tamarind seed xyloglucan (XG) is a natural neutral hemicellulose and a hydrophilic polysaccharide consisting of a main chain of glucan backbone with xylose and galactose side chains. XG is endowed with idiosyncratic mucoadhesive and in situ gelling properties which rated XG as an attractive, functional polymer for numerous drug delivery applications. In milieu of this, the present review is designed to underline the plausible potential of XG or XG-based systems in drug delivery. The feasibility of surface-tailoring, the flexibility of chemical-modification, and the possibility as ligand-conjugations grant XG an extraordinary consideration in the scientific territory. The authors are hopeful that the versatility of XG would meet the expectations of regulatory authorities and the XG-based products will serve the therapeutic needs of the community in the future, if sufficiently investigated and promising outcomes are obtained in human subjects.

A series of new sulphonamido-quinoxaline derivatives 3 ( a – p ) have been prepared which are structurally similar to the High Throughput Screening (HTS) hit identified by Porter and collaborator. The newly synthesized compounds 3b , 3c , 3f , 3i , 3j , 3l , 3n and 3o were further evaluated in the National Cancer Institute for in vitro cytotoxicity assay among them compound 3l showed highest activity against Leukemia RPMI-8226 cell lines (GI 50 : 1.11 μM) as compared to other tested compounds. It is to be noted that compound 3l shows significant activity (GI 50 : 1.11 μM) compared to the High Throughput Screening (HTS) hit identified by Porter and collaborator (IC 50 = 1.3 μM). Further docking study confirms the c-Met kinase inhibitory mechanism of the synthesized compounds.

New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.

In this study, some novel 2,6-disubstituted imidazo[2,1- b ][1,3,4]thiadiazoles 4 ( a – i ), 7 ( a – p ) and 11 ( a – i ) were synthesized from 5-substituted-1,3,4-thiadiazol-2-amine. The newly synthesized compounds 4a , 4b , 4c , 4e , 4g , 7j , 7l , 11b and 11c were evaluated in the National Cancer Institute for single dose in vitro primary cytotoxicity assay. Among the tested nine compounds, compound 4b (107166/760239) and 4c (107168/760240) were passed the criteria for activity in this assay and scheduled automatically for evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. 3-(2-(4-methoxyphenyl)imidazo[2,1- b ][1,3,4]thiadiazol-6-yl)aniline ( 4c ) exhibited significant in vitro anticancer activity against Non Small Cell Lung Cancer HOP-92 cell line (GI 50 : 0.114 μM) and Renal Cancer CAKI-1 cell line (GI 50 : 0.743 μM).

A series of 2,5,6-trisubstituted imidazo[2,1- b ][1,3,4]-thiadiazole derivatives 4 ( a – k ) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5 ( a – k ) and 5-thiocyanato 6 ( a – k ) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, 1 H NMR, 13 C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10 −5 M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1- b ][1,3,4]thiadiazole 5b ( NSC D - 96022 / 1 ) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

In this paper, an attempt was made to develop a Quantitative Structure Activity Relationship (QSAR) model on a series of quinazoline derivatives acting as Protein tyrosine kinases (erbB-2) inhibitors using Multiple Linear Regression, Principal Component Regression and Partial Least Squares Regression methods. Among these three methods, Multiple Linear Regression (MLR) method has come out with a very promising result as compared to other two methods. Various 2D descriptors were calculated and used in the present analysis. For model validation, the dataset was divided into training and test sets using spherical exclusion method. The developed MLR- QSAR model was found to be statistically significant with respect to training (r2 =0.956), cross-validation (q2 = 0.915), and external validation (pred_r2= 0.6170). The developed MLR model suggests that Estate Contribution descriptors SaaOE-Index (30.07%) and SsCIE-index (15.79%) are the most important descriptors in predicting Tyrosine kinase (erbB-2) inhibitory activity. Electron withdrawing group at 4th position of quinazoline enhances the activity as evident by positive value of SsClE-index (15.79). In addition, for quinazoline substituents, estate contribution descriptors SsCH3E – index has a large deactivating effect.

Although chitosan (CHT, a linear cationic polysaccharide) is biodegradable, biocompatible, non-toxic, and mucoadhesive in nature, the low solubility of CHT in aqueous and alkaline media limits its applicability in pharmaceutical and biomedical field. This necessitate the introduction of new chemically-modified derivatives of CHT those can surmount the solubility barrier. Herein, N,N,N-trimethyl chitosan (TMC), a quaternized hydrophilic derivative of CHT, was synthesized by two-step reductive methylation of CHT and characterized for 1H NMR and zeta potential measurements. Polyelectrolyte complexes (PECs) based on TMC and dextran sulfate (DS) were prepared via ionic interactions between charged functional groups of former polysaccharides at different pH conditions (pH 5, 8, 10, and 12) and characterized for physicochemical (particle size and zeta potential) and solid- state characterizations (HR-TEM, SEM, FTIR, TGA and XRD). At alkaline pH conditions, the participant polymer chains (TMC and DS) are sufficiently close to form more stable PECs. The release efficiency was assessed after loading a model drug into optimized PEC formulation. Data indicated that the PECs fabricated at alkaline pH presents a reliable formulation for pharmaceutical and biomedical applications.

Pentacyclic Triterpenoids (PTs) and their analogues as well as derivatives are emerging as important drug leads for various diseases. They act through a variety of mechanisms and a majority of them inhibit the nuclear factor kappa-beta (NF-κB) signaling pathway. In this study, we examined the effects of the naturally occurring PTs on IκB kinase-β (IKKβ), which has great scientific relevance in the NF-κB signaling pathway. On virtual screening, 109 PTs were screened through the PASS (prediction of activity spectra of substances) software for prediction of NF-κB inhibitory activity followed by docking on the NEMO/IKKβ association complex (PDB: 3BRV) and testing for compliance with the softened Lipinski's Rule of Five using Schrodinger (LLC, New York, USA). Out of the projected 45 druggable PTs, Corosolic Acid (CA), Asiatic Acid (AA) and Ursolic Acid (UA) were assayed for IKKβ kinase activity in the cell free medium. The UA exhibited a potent IKKβ inhibitory effect on the hotspot kinase assay with IC50 of 69 μM. Whereas, CA at 50 μM concentration markedly reduced the NF-κB luciferase activity and phospho-IKKβ protein expressions. The PTs tested, attenuated the expression of the NF-κB cascade proteins in the LPS-stimulated RAW 264.7 cells, prevented the phosphorylation of the IKKα/β and blocked the activation of the Interferon-gamma (IFN-γ). The results suggest that the IKKβ inhibition is the major mechanism of the PTs-induced NF-κB inhibition. PASS predictions along with in-silico docking against the NEMO/IKKβ can be successfully applied in the selection of the prospective NF-κB inhibitory downregulators of IKKβ phosphorylation.

In this research work, a series of eighteen novel coumarinyl substituted thiazolidin-2,4-dione analogs (4a-4r) have been designed by molecular hybridization approach, synthesized and their structures were established on the basis of FTIR, 1H NMR, 13C NMR and elemental (CHN) analysis. These title compounds were screened for their cytotoxicity using MTT assay methodology against five different mammalian cancer cell lines viz. hormone dependant breast adenocarcinoma (MCF7), cervical carcinoma (HeLa), colorectal carcinoma (HT29), lung cancer (A549) and prostate adeno carcinoma (PC3). The cytotoxicity screening studies revealed that MCF-7, HeLa and A549 cancer cell lines were sensitive to all the tested compounds. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most significant effect was observed for compounds 4i (1.06, 2.4 and 3.06 µM) and 4o (0.95, 3.2 and 2.38 μM) against MCF7, HeLa and A549 cell lines respectively. In conclusion, the anticancer results of these promising leads strongly encouraged us for additional lead optimization with the aim of developing more potential anticancer agents.

Azetidin-2-one, a β -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.

A new series of imidazo[2,1- b ][1,3,4]thiadiazoles 5 ( a – g ), 6 ( a – g ), 9 ( a – i ) and 12 ( a – h ) were synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d , 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC 50 = 0.0012 μM) and elective inhibition (91%) against the P38αkinase at10 μM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50 = 0.03 μm), 5t (IC50 = 0.03 μm), 4s (IC50 = 0.07 μm), and 5n (IC50 = 0.01 μm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50 = 1.8 μm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50 = 83.1 to 231.8 μm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF-1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r(2) = 0.9469 and cross validated squared correlation coefficient q(2) = 0.8933 with external predictive ability of pred_r(2) = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q(2) = 0.9672 and pred_r(2) = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity.