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Four different simple, accurate and precise UV-spectrophotometric methods have been developed for the estimation of palbociclib (PB) in bulk and in-house capsule dosage form by zero order (Method I), zero order AUC (Method II), ‘first order derivative UV-spectrophotometric (Method III), and first order AUC (Method IV) methods. The drug was dissolved in methanol (AR-Grade) and further dilution was made in double distilled water. Zero order was performed at λ max 220.00 nm of PB (Method I) and AUC was calculated between 215.40 nm - 228.20 nm wavelength (Method II). In Method-III zero-order spectra were derivatized into first-order and amplitude measured at 231.00 nm and the AUC was recorded between 224.00 nm - 240.60 nm (Method IV). PB followed linearity in the concentration range of 4.08-20.40 µg/mL with correlation coefficient (r2 )> 0.99 for PB.

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.

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.

The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5 mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50 mM/kg/day dose for 5 days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30 min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1β production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (− 5.636 kcal/mol) and highest binding free energy (ΔG bind − 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00086-x.

Background: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. Material and Method: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17a to AR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. Result: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20 mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25 μg/mL for inhibition of bacteria by most of the compounds. Conclusion: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections. Keywords: Imidazothiazole, Fluoroquinolone, Anti-Inflammatory, Antibacterial, MIC

In the current research, methaqualone derivatives were synthesized and assessed for their anti-convulsant activity. Among them, compounds 3, 4, 6, 7 and 11 exhibited significant anti-convulsant activities with ED50 values of 132.23 mg/kg, 120.34 mg/kg, 100.78 mg/kg, 145.89 mg/kg, and 148.46 mg/kg, respectively. The toxicity profiling (TD50) of these compounds (3, 4, 6, 7 and 11) demonstrated that these drugs caused only a minor neurological impairment. The PI scores of these compounds (3, 4, 6, 7 and 11) were higher than the reference drug (methaqualone PI: 1.99). The acetylcholinesterase enzyme level is significantly reduced in these compounds, indicating the enhancement of cognition activity. Pharmacophoric modelling and molecular docking studies against the human GABA-A receptor are in close agreement with each other. Molecular dynamic simulation of compound 6 indicates that it remains stable with the human GABA-A receptor for a 100 ns time span.

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.

Tuberculosis (TB) transmitted by Mycobacterium tuberculosis (Mtb) is one of the top 10 causes of death globally. Currently, the widespread occurrence of resistance toward Mtb strains is becoming a significant concern to public health. This scenario exaggerated the need for the discovery of novel targets and their inhibitors. Targeting the “Mtb cell wall peptidoglycan synthesis” is an attractive strategy to overcome drug resistance. Mur enzymes (MurA-MurF) play essential roles in the peptidoglycan synthesis by catalyzing the ligation of key amino acid residues to the stem peptide. These enzymes are unique and confined to the eubacteria and are absent in humans, representing potential targets for anti-tubercular drug discovery. Mtb Mur ligases with the same catalytic mechanism share conserved amino acid regions and structural features that can conceivably exploit for the designing of the inhibitors, which can simultaneously target more than one isoforms (MurC-MurF) of the enzyme. In light of these findings in the current review, we have discussed the recent advances in medicinal chemistry of Mtb Mur enzymes (MurA-MurF) and their inhibitors, offering attractive multi-targeted strategies to combat the problem of drug-resistant in M. tuberculosis.

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.

A series of novel quinazoline derivatives were synthesized, virtually screened through different filters and evaluated for their anticonvulsant activity against electrically and chemically induced seizures, compared with that of the standard drugs methaqualone and sodium valproate. Compound 48, 3-(2-aminophenyl)-7-chloro-2-phenylquinazolin-4(3H)-one, was found to be the most potent compound of the series accompanied by relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that compounds 12, 48, 49 and 50 could be useful templates for future design, optimization, and investigation to construct more active analogs.

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.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. A library of 6,7-dimethoxy quinazoline was prepared using a ligand based drug design approach and passed through different filters of virtual screening such as a docking study and Lipinski's rule. Twenty virtually screened compounds were synthesized and investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Virtually screened compound 47 having 4-chlorophenyl-1,3,4-thiadiazole substitution at 3rd position of 6,7-dimethoxy-2-phenylquinazolin-4-(3H)-one exhibited the most promising activity, with IC50 values of 3.8 nm and 5.5 nm against VEGFR-2 tyrosine kinase and the HUVEC cell line. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2 demonstrating that compound 47 is a potential agent for cancer therapy that deserves further research.

A novel series of methyl-2-(substituted benzylideneamino)-3-phenyl propionate (2a–j) derivatives have been synthesized. The title compounds (2a–j) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg b.w. Compound 2e exhibited the most promising and significant anti-inflammatory profile while compounds 2b, 2h, 2i, and 2j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid-induced writhing model) and antipyretic activity (yeast-induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. The synthesized compounds were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by in vitro colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 2b, 2e, 2h, 2i, and 2j exhibited selective and effective inhibition against COX-2. In an attempt to understand the ligand–protein interactions in terms of their binding affinity, docking studies were also performed using Molegro Virtual Docker (MVD-2013, 6.0) for the title compounds. It was observed that the binding affinities calculated were in agreement with the experimental IC50 values.

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.

A novel series of 2,5,6-trisubstituted imidazo[2,1- b ][1,3,4]thiadiazoles 4 ( a – d ) and 7 ( a – i ) were rationally designed through QSAR based pharmacophore approach and synthesized from 5-(1,3-benzodioxol-5-yl)-[1,3,4]thiadiazol-2-amine ( 1 ). The structures of these compounds were established by IR, 1 H NMR, 13 C NMR, HRMS technique. All the compounds were evaluated for their in vitro antihyperlipidemic activity using trition induced hyperlipidemic model. The newly synthesized title compound 7d , 7e and 7h showed a significant decrease in the serum, TCH, TG LDL and VLDL values along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, LDL:HDL risk ratios and the level of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group.

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.

Dextromethorphan (DXM) and diphenhydramine (DPH) are two commonly used over-the-counter non-narcotic antitussive drugs. Recent reports reveal the widespread abuse of DXM and DPH due to their euphoric and alcohol-like effects. Due to their medicinal importance as well as the apparent increase in their use as abused drugs, it has become critical to determine them in samples of biological, clinical and pharmaceutical interest. The electrochemical techniques for drug analysis have gathered considerable attention due to their pronounced selectivity, sensitivity and simplicity. The given review presents a compilation of published voltammetric and potentiometric methods developed for determination of DXM and DPH. It critically highlights the analytical performances, revealing the recent trends and progress in the specified approach for their analysis. The review forms a basis for further progress in this field and development of improved electrochemical sensors to determine the drug.

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.

A series of 6-bromo-2-ethyl-3-(substitutedbenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one 3 ( a – j ) were synthesized using appropriate synthetic route and evaluated experimentally by the Maximal Electro Shock (MES) and the PTZ-induced seizure methods. Among the tested compounds, 3-(benzo[ d ]thiazol-2-yl)-6-bromo-2-ethylquinazolin-4(3 H )-one ( 3a ) has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6-methoxybenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one ( 3h ) against clonic seizure by PTZ-induced seizure model. Not one of the selected compounds demonstrated any sign of neurotoxicity and hepatotoxicity.

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.