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SO2 is emerging as a possible endogenous signaling molecule in mammals. In addition, SO2 has also shown pharmacological effects, presenting SO2 as a promising potential therapeutic agent. The past decade has witnessed steady advances in the development of small molecule-based SO2 prodrugs/donors with varied release mechanisms. Herein, we summarize various strategies employed for SO2 prodrug design. The remaining challenges and issues will also be discussed.

Antibiotic-resistant bacteria represent a serious threat to modern medicine and human life. Only a minority of antibacterial agents are active against Gram-negative bacteria. Hence, the development of novel antimicrobial agents will always be a vital need. In an effort to discover new therapeutics against Gram-negative bacteria, we previously reported a structure-activity-relationship (SAR) study on 1,2-disubstituted benzimidazole derivatives. Compound III showed a potent activity against tolC-mutant Escherichia coli with an MIC value of 2 μg/mL, representing a promising lead for further optimization. Building upon this study, herein, 49 novel benzimidazole compounds were synthesized to investigate their antibacterial activity against Gram-negative bacteria. Our design focused on three main goals, to address the low permeability of our compounds and improve their cellular accumulation, to expand the SAR study to the unexplored ring C, and to optimize the lead compound (III) by modification of the methanesulfonamide moiety. Compounds (25a-d, 25f-h, 25k, 25l, 25p, 25r, 25s, and 26b) exhibited potent activity against tolC-mutant E. coli with MIC values ranging from 0.125 to 4 μg/mL, with compound 25d displaying the highest potency among the tested compounds with an MIC value of 0.125 μg/mL. As its predecessor, III, compound 25d exhibited an excellent safety profile without any significant cytotoxicity to mammalian cells. Time-kill kinetics assay indicated that 25d exhibited a bacteriostatic activity and significantly reduced E. coli JW55031 burden as compared to DMSO. Additionally, combination of 25d with colistin partially restored its antibacterial activity against Gram-negative bacterial strains (MIC values ranging from 4 to 16 μg/mL against E. coli BW25113, K. pneumoniae, A. baumannii, and P. aeruginosa). Furthermore, formulation of III and 25d as lipidic nanoparticles (nanocapsules) resulted in moderate enhancement of their antibacterial activity against Gram-negative bacterial strains (A. Baumannii, N. gonorrhoeae) and compound 25d demonstrated superior activity to the lead compound III. These findings establish compound 25d as a promising candidate for treatment of Gram-negative bacterial infections and emphasize the potential of nano-formulations in overcoming poor cellular accumulation in Gram-negative bacteria where further optimization and investigation are warranted to improve the potency and broaden the spectrum of our compounds.

The COVID-19 pandemic caused by SARS-CoV-2 has demonstrated the potential of emergent pathogens to severely damage public health and global economies. As a consequence of the pandemic, millions of people have been forced into self-isolation, which has negatively affected the global economy. More efforts are needed to find new innovative approaches that could fundamentally change our understanding and management of this disaster. Herein, lipid polymer hybrid nanoparticles (LPH NPs) were utilized as a platform for the delivery of azithromycin or niclosamide in combination with piroxicam. The obtained systems were successfully loaded with both azithromycin and piroxicam (LPHAzi–Pir) with entrapment efficiencies (EE%) of 74.23 ± 8.14% and 51.52 ± 5.45%, respectively, or niclosamide and piroxicam (LPHNic–Pir) with respective EE% of 85.14 ± 3.47% and 48.75 ± 4.77%. The prepared LPH NPs had a core–shell nanostructure with particle size ≈ 125 nm and zeta potential ≈ −16.5 irrespective of drug payload. A dose-dependent cellular uptake of both LPH NPs was observed in human lung fibroblast cells. An enhanced in vitro antiviral efficacy of both LPHAzi–Pir and LPHNic–Pir was obtained over the mixed solution of the drugs. The LPH NPs of azithromycin or niclosamide with piroxicam displyed a promising capability to hinder the replication of SARS-CoV-2, with IC50 of 3.16 and 1.86 μM, respectively. These results provide a rationale for further in vivo pharmacological as well as toxicological studies to evaluate the potential activity of these drugs to combat the COVID-19 outbreak, especially the concept of combination therapy. Additionally, the molecular docking of macrolide bioactive compounds against papain-like protease (PDB ID:6wuu) was achieved. A ligand-based study, especially rapid overlay chemical structure (ROCS), was also examined to identify the general pharmacophoric features of these compounds and their similarity to reported anti-SARS-CoV-2 drugs. Molecular dynamic simulation was also implemented.

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

A facile and efficient One-pot procedure was achieved for the synthesis of thiazol-2(3H)-imine derivatives through the bromination of some α-active methylene ketones followed by treatment with potassium thiocyanate and condensation with various primary amines in ethanol as one-pot four-step process. The α-active methylene ketones were symmetrical and asymmetrical ketones. The primary amines used were mostly aromatic amines and also benzylamine was used. This proposed method does not require the use of techniques such as extraction and chromatography. Surprisingly, the product from the reaction of 3-thiocyanacetylacetone and benzylamine was elucidated to be N-(3-benzyl-4-hydroxy-4-methylthiazolidin-2-ylidene)acetamide (2) and not the expected compound 1-(3-benzyl-2-imino-4-methyl-2,3-dihydrothiazol-5-yl)ethan-1-one (1),which was proved based on the existence of the methylene and hydroxyl group in the compound.The mechanism of the novel compound 2 was confirmed by subsequent chemical reactions, spectroscopic data and X-ray crystallography.The molecular structure of all newly synthesized thiazol-2(3H)-imine derivatives were elucidated on the basis of spectroscopic dataand elemental analysis.

A series of novel anticancer hydrazinotriazolothiadiazine-based derivatives were designed based on the structure–activity relationship of the previously reported anticancer triazolothiadiazines. These derivatives were synthesized and biologically screened against full NCI-60 cancer cell lines revealing compound 5l with a potential antiproliferative effect. 5l was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β) with IC50 equal to 0.883 μM and 14-fold selectivity over CDK2. Also, 5l increased active caspase-3 levels, induced cell cycle arrest at the G2-M phase, and increased the percentage of Annexin V-fluorescein isothiocyanate-positive apoptotic cells in PC-3 prostate cancer-treated cells. Molecular docking and dynamics were performed to predict the binding mode of 5l in the GSK-3β ATP binding site. 5l can be utilized as a starting scaffold for developing potential GSK-3β inhibitors.

Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-d]pyrimidine based urea derivative, KM6. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. KM6 retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, KM6 reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, KM6 is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms., Graphical Abstract

[Image: see text] Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound 1), we identified a closely related derivative, compound 2, which exhibited cogent antitumor activities while devoid of compound 1’s ability to promote EGFR/c-Met degradation. Compound 2 acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1. However, it did not alter the phosphorylation status of MST1/2, a LATS1 kinase, suggesting an alternative mechanism for LATS1 activation. Orally administered compound 2 was effective in suppressing MDA-MB-231 xenograft tumor growth while exhibiting a satisfactory safety profile. From a therapeutic perspective, compound 2 might help foster new therapeutic strategies for cancer treatment by restoring the Hippo pathway regulatory function to facilitate YAP degradation.

Herein, we report an eco-friendly synthesis of a new series of quinazolinone-based derivatives as potential PARP-1 inhibitors. The 4-quinazolinone scaffold was utilized as a bioisostere to the phthalazinone core of the reference compound Olaparib. Most of the synthesized compounds displayed appreciable inhibitory activity against PARP-1. Compound 12c showed inhibitory activity at IC50 = 30.38 nM comparable to Olaparib, which has IC50 = 27.89 nM. Cell cycle analysis was performed for compounds 12a and 12c, and both exhibited cell growth arrest at G2/M phase in the MCF-7 cell line. In addition, both compounds increased the programmed apoptosis compared to the control. Furthermore, molecular docking of the final compounds into the PARP-1 active site was executed to explore their probable binding modes. Also, a computational QSAR and in silico ADMET study was performed. The results of this study revealed that some of the newly synthesized compounds could serve as a new framework to discover new PARP-1 inhibitors with anti-cancer activity.

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP, that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC

A series of pyrrolo[2,3-d]pyrimidine linked to diarylureas were previously discovered by our group as sorafenib fused congeners, which were endowed with more potent activity as inhibitors to vascular endothelial growth factor receptor (VEGFR2) than sorafenib. Based on these results and on the observation that the fluorinated regorafenib displayed higher VEGFR2 inhibitory activity relative to sorafenib. Therefore, in this study, we sought to develop more potent pyrrolopyrimidine surrogates through introduction of fluorine atom at the phenyl moiety near to the urea moiety mimicking regorafenib. We hypothesized that this would improve the compounds potency. Surprisingly, Compound9epossessed better VEGFR2 inhibitory activity (IC

Objectives: The continuous reporting of bacterial resistance to antibiotics is an ongoing challenge that can be life-threatening. Actions to develop new chemicals to overcome the bacterial resistance has gained a significant importance. Methods: A series of ketene S,N-acetals 4a-k and their pyrazoles 6a-k were synthesized and their structures were established by spectral data. Membrane permeability predictions and in vitro antimicrobial activity against multi-drug resistant (MDR) Gram-positive bacteria and other microorganisms was determined. The binding affinity with DNA gyrase was assessed using in silico studies in comparison to ciprofloxacin then tthe gyrase inhibition assay was conducted to detect the mode of action. Results: All the synthesized compounds have a good affinity to pass through the phospholipid membrane of Staphylococcus aureus (S. aureus). Compound 6g exhibited the most potent antibacterial activity with MIC values ranged between 16 and 32 µg/mL. The compound also showed a higher binding affinity than ciprofloxacin with DNA gyrase in the in silico studies and this effect was clearly shown by a very good IC50 value of the gyrase inhibition assay. Conclusions: According to our data, compound 6g is a possible candidate to act against MDR bacteria and its main mode of action is through inhibition of the gyrase enzyme, further modifications are still required to enhance its activity.

The antibiotic resistance of methicillin-resistant Staphylococcus aureus (MRSA) is attributable to the expression of the high molecular mass transpeptidase enzyme, penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the cross-linking reaction step in the cell wall biosynthesis in the face of the challenge by β-lactam antibiotics. In the current study, ten pyrazole and benzimidazole based-compounds were designed, synthesized, and evaluated as anti-MRSA agents. These derivatives were screened for their antibacterial activity against two Staphylococcus (S.) aureus strains; methicillin-sensitive Staphylococcus aureus (MSSA) ATTC6538 and MRSA USA300 strains. Three of the tested compounds (XII, XIII, and XIV) exhibited moderate bactericidal activity against MSSA, MRSA, and vancomycin-resistant Staphylococcus aureus (VRSA) strains. Docking of these compounds into the allosteric site of PBP2a showed comparable binding modes to that of the lead quinazolinone PBP2a inhibitors suggesting a similar mode of action. The present study presents a promising candidate for further optimization as a potential PBP2a inhibitor targeting MRSA infection.

Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.

In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.

Corticotrophin releasing factor receptor-1 (CRFR1) is a potential target for treatment of depression and anxiety through modifying stress response. A series of new thiazolo[4,5-d]pyrimidine derivatives were designed, prepared and biologically evaluated as potential CRFR1 antagonists. Four compounds produced more than fifty percent inhibition in the [125I]-Tyr0-sauvagine specific binding assay. Assessment of binding affinities revealed that compound (3-(2,4-dimethoxyphenyl)-7-(dipropylamino)-5-methylthiazolo[4,5-d]pyrimidin-2(3H)-one) 8c was the best candidate with highest binding affinity (Ki = 32.1 nM). Further evaluation showed the ability of compound 8c to inhibit CRF induced cAMP accumulation in a dose response manner. Docking and molecular dynamics simulations were used to investigate potential binding modes of synthesized compounds as well as the stability of 8c-CRFR1 complex. These studies suggest similar allosteric binding of 8c compared to that of the co-crystalized ligand CP-376395 in 4K5Y pdb file.

A series of novel 3-allyl-2-iminothiazolidin-4-one derivatives (4-17) was synthesized, through the reaction of 3-allyl-2-((3,4-dichlorophenyl)imino)thiazolidin-4-one (3) with different aromatic aldehydes. The chemical stability of four representative thiazolidinone derivatives (3, 11, 13 and 14) was evaluated against γ-irradiation, at a radiation dose of 25 kGy. The compounds were found to be stable with no observed degradation in liquid chromatography–mass spectrometry (LC-MS) experiments. The synthesized thiazolidinone derivatives (3-17) were evaluated for their antimicrobial and anticancer activities. Among the tested compounds, compounds 5, 7, 8, 14 and 16 exhibited slight antibacterial activity against a multi-drug resistant Staphylococcus aureus (ATCC 43300 strain), at a concentration of 32 µg/mL. Compound 3 fully inhibited the growth of the fungal pathogen Cryptococcus neoformans, at a tested concentration of 32 µg/mL. Besides, compound 12 inhibited the biofilm formation of S. aureus (HG001 strain), with a percentage of 54% at a concentration of 64 µg/mL. Compared to the other tested compounds, compound 11 showed higher in vitro anticancer activity against melanoma and breast cancer cells, with growth inhibition values ranging from 42% to 73% at a concentration of 10 µM. Interestingly, only compounds 3, 8 and 16 showed weak cytotoxicity to murine fibroblast L929 cells, at a tested concentration of 100 µM. The other tested compounds were not cytotoxic to fibroblasts, which suggests the relative safety of the synthesized compounds to normal mammalian cells.

Graphical abstract, This work was a structured virtual screening for marine bioactive compounds with reported antiviral activities which were subjected to structure-based studies against SARS-CoV-2 co-crystallized proteins. The molecular docking of marine bioactive compounds against the main protease (Mpro, PDB ID: 6lu7 and 6y2f), the spike glycoprotein (PDB ID: 6vsb), and the RNA polymerase (PDB ID: 6m71) of SARS-CoV-2 was performed. Ligand-based approach with the inclusion of rapid overlay chemical structures (ROCS) was also addressed in order to examine the probability of these marine compounds sharing relevance and druggability with the reported drugs. Among the examined marine library, the highest scores in different virtual screening aspects were displayed by compounds with flavonoids core, acyl indole, and pyrrole carboxamide alkaloids. Moreover, complete overlay with the co-crystallized ligands of Mpro was revealed by sceptrin and debromo-sceptrin. Thalassoilin (A-B) which found in the Red Sea exhibited the highest binding and similarity outcomes among all target proteins. These data highlight the importance of marine natural metabolites in regard of further studies for discovering new drugs to combat the COVID-19 pandemic.

Vascular endothelial growth factor receptor (VEGFR) is one of the well-known targets that control angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the new compounds were also designed to interact with residues in the solvent accessible region such as Asn923. Accordingly, the thienopyrimidine target compounds were synthesized and subjected to VEGFR-2 enzyme inhibition assay. Several target compounds (7d-f, 8b-c, 8e-g and 15c) exhibited potent inhibitory activities against VEGFR-2 with IC50 values in low nanomolar range. Compounds 8b and 8e revealed exceptionally potent inhibitory activity with IC50 of 5 and 3.9 nM, respectively. The molecular docking analysis and molecular dynamics simulation were also performed to further investigate these findings.

Epigenetic markers of the cellular genome are major controllers of the transcriptional level of various genes in physiological and pathological states. These markers are written and erased by epigenetic factors which have been recently studied as potential therapeutic targets of various disease states. Histone lysine demethylases are an example of these epigenetic factors. The subfamily number 6 of these enzymes (KDM6) are an understudied group of histone demethylases which have been recently connected to cancers and inflammation. In this work, we conducted a rational and computer-aided approach to design and synthesize KDM6 inhibitors. The designed inhibitors are imidazole-based and are functionalized with variable metal-chelating group to be able to chelate the active site ferrous ion. One of the synthesized compounds, compound 6, was able to inhibit KDM6-expressing cancer cell lines by more than 50%. Molecular docking studies suggest that this compound is able to achieve important active site interactions and coordinate the active site metal through a tridentate interaction. Furthermore a correlation was established between the structural features and CLogP of the tested compounds and their activity. These results represent a promising starting point for the future development of novel KDM6 inhibitors with higher potency.

Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC50 values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.

New thiazolo[4,5-d]pyrimidine analogues were synthesized and biologically assessed in-vitro for their antineoplastic activity. The growth inhibitory effects of these compounds were assessed through the National Cancer Institute-United States of America (NCI-USA) anticancer screening program. Compound 5 (7-Chloro-3-(2,4-dimethoxyphenyl)-5-methylthiazolo[4,5-d]pyrimidine-2(3H)-thione) was found to have a potent and broad-spectrum cytotoxic action against NCI panel with GI50 (50% growth inhibition concentration) mean graph midpoint (MG-MID) = 2.88 µM. MTT assay was used to determine IC50 values of the most potent agent against HCT-116 colorectal carcinoma and WI-38 human lung fibroblast cell lines; 5.33 µM ± 0.69 and 21.69 µM ± 1.04, respectively. Flow cytometric analysis revealed that compound 5 triggered apoptosis and G2/M cell cycle arrest. The ability of compound 5 to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyclin B complex was evaluated, and its IC50 value was 97 nM ± 2.33. Moreover, according to the gene expression analysis, compound 5 up-regulated p53, BAX, cytochrome c, caspases-3,-8 and-9 besides down-regulated Bcl-2. In conclusion, compound 5 exerted a potent pro-apoptotic activity through the activation of the intrinsic apoptotic pathway and arrested the cell cycle at the G2/M phase.

A new series of sixteen new 2-arylamino-5,7-disubstituted-N-aryl-pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives was designed and synthesized. The antitumor activities of the new compounds were initially screened through the developmental therapeutics program at NCI-USA 60 cell line panel. 2-((2,4-dimethoxyphenyl)amino)-5,7-diphenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7a) was identified as a potential hit with a mean percentage of growth inhibition of 48.5% over the 60-NCI cancer cell lines whereas the other fifteen compounds ranged from 0.5 to 10.72%. In MTT assay, compound 7a exhibited IC

Nuclear Estrogen receptors (ER) are cytoplasmic proteins; translocated to the nucleus to induce transcriptional signals after getting bound to the estrogen hormone. ER activation implicated in cancer cell proliferation of female reproductive organs. Thus, the discovery of ER antagonists is a reliable strategy to combat estrogen-dependent breast cancer. Endometrial carcinoma is one of the complications encountered upon long-term therapy by selective estrogen receptor modulators (SERMs) like Tamoxifen (TMX) and methyl piperidinopyrazole (MPP). Thus, the ER-full antagonist is a solution to improve the safety of this class of therapeutics during the treatment of breast cancer. We selected MPP as a lead structure to design conformationally constrained analogs. Structural rigidification is a proven strategy to transform the SERMs into full antagonists. Accordingly, we synthesized 7-methoxy-3-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[g]indazoles (4), (6a-c),(8-12) along with the biphenolic counterparts(13-19)that are the anticipated active metabolites. The 4-nitrophenyl derivative(4)is with the most balanced profile regardingthe in vivoanti-uterotrophic potential (EC

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC50 values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent.

In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.

Pyrrolopyrimidine derivatives comprise a class of biologically active heterocyclic compounds that are well known to play a critical role in pharmaceutical drug design and health care. The pyrrolopyrimidines serve as promising scaffolds that were found in a number of biologically active compounds including antibiotics, anti-inflammatory, anti-viral and anticancer. Researchers were inspired to develop novel pyrrolopyrimidine derivatives for the treatment of Cancer. Currently several pyrrolopyrimidines are available commercially as anticancer drugs. The present review article offers a detailed account on the development of pyrrolopyrimidine derivatives with anticancer potential with emphasis on their activity as targeted kinase inhibitors.

Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3- d ]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c) , the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC 50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10 . This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).

Despite the increased success rates of histone deacetylases inhibitors (HDACi) as potent anticancer agents, many metabolic obstacles face the hydroxamic acid-based HDAC inhibitors, which inspired us to develop non-hydroxamate HDAC inhibitors. Based on the established knowledge of the SAR of the reported HDAC inhibitors and based on the knowledge that salicylaldimine moiety is an established chelating agent, a series of salicylaldimine based HDAC inhibitors were designed, synthesized and biologically evaluated. The compound 14 in the present study showed considerable HDAC inhibition and potential antiproliferative activities on NCI cell lines rendering it as a good start for optimization that introduces a new class of non-hydroxamate HDAC inhibitors as potential anticancer agents.

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC50 = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC50 = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a‘s ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition.

Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.

Herein, we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric CXCR2 inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2 with IC50 less than 10 M and selectivity over CXCR4. Our ADMET simulations suggest favorable drug-like properties for the active compounds. Importantly, we developed a predictive model that can distinguish active from inactive compounds and will serve as a valuable tool to guide the design of optimized compounds to be evaluated in preclinical models.

Employing an intramolecular cycloaddition reaction, we have developed a series of SO2 prodrugs with tunable release rates with half-lives ranging from minutes to days.

Antimicrobial resistance is an imminent threat worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the "superbug" family, manifesting resistance through the production of a penicillin binding protein, PBP2a, an enzyme that provides its transpeptidase activity to allow cell wall biosynthesis. PBP2a's low affinity to most β-lactams, confers resistance to MRSA against numerous members of this class of antibiotics. An Achilles' heel of MRSA, PBP2a represents a substantial target to design novel antibiotics to tackle MRSA threat via inhibition of the bacterial cell wall biosynthesis. In this review we bring into focus the PBP2a enzyme and examine the various aspects related to its role in conferring resistance to MRSA strains. Moreover, we discuss several antibiotics and antimicrobial agents designed to target PBP2a and their therapeutic potential to meet such a grave threat. In conclusion, we consider future perspectives for targeting MRSA infections.

A series of 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles 11a–j and 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 16a–c was synthesized by the reaction of 5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (5) with 3-(dimethylamino)-1-arylprop-2-en-1-ones 6a–j or 2-aryl-3-(dimethylamino)acrylonitriles 12a–c, respectively. In addition, 7-amino-5-oxo-2-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (22) was prepared from the reaction of compound 5 with ethyl cyanoacetate. The anticancer activity of the newly synthesized compounds against Huh-7, HeLa, MCF-7 and MDA-MB231 cell lines showed moderate activity of compound 11f as anti-proliferative agent against Huh-7 cell line with IC50 = 6.3 µM when compared with doxorubicin (IC50 = 3.2 µM). On the other hand, compound 16b revealed potent anti-proliferative activity against HeLa cell line with IC50 = 7.8 µM when compared with doxorubicin (IC50 = 8.1 µM). Also compound 11i exhibited a promising anti-proliferative activity against MCF-7 cell line (IC50 = 3.0 µM) whereas IC50 of doxorubicin = 5.9 µM, finally compounds 11i and 16b have potent activity as anti-proliferative agents against MDA-MB231 cell line with IC50 = 4.32 and 5.74 µM, respectively when compared with doxorubicin (IC50 = 6.0 µM).

Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.

Being overexpressed in several types of cancer, the epidermal growth factor receptor (EGFR) is considered one of the key therapeutic targets in oncology. Although many first-generation EGFR inhibitors had been FDA approved for the treatment of certain types of cancer, patients soon developed resistance to these reversible ATP competitive inhibitors via mutations in the kinase domain of EGFR. A new trend was adopted to design covalent irreversible inhibitors, that is, second- and third-generation inhibitors. Second-generation inhibitors can inhibit the mutant forms but, unfortunately, they had dose limiting side effects due to wild-type EGFR inhibition. Third-generation inhibitors emerged shortly, which were capable of inhibiting the mutant forms exclusively while sparing the wild type. Many other strategies have also been developed to reduce the risk of covalent interactions with off-targets, thus improving the pharmacokinetic and/or pharmacodynamic profile of the antiproliferative agents. In this review, we focused mainly on second- and third-generation EGFR inhibitors, their binding mechanisms (either docking studies or co-crystallized structures), their synthetic approaches, clinical profiles, and limitations.

Quinoxaline derivatives, also called benzopyrazines, are an important class of heterocyclic compounds. Quinoxalines have drawn great attention due to their wide spectrum of biological activities. They are considered as an important basis for anticancer drugs due to their potential activity as protein kinase inhibitors. In this review, we focus on the chemistry of the quinoxaline derivatives, the strategies for their synthesis, their potential activities against various tyrosine kinases, and on the structure-activity relationship studies reported to date.

Three series of novel indazole–pyrimidine based compounds were designed, synthesized and biologically evaluated as VEGFR-2 kinase inhibitors. The most active compound 6i (IC50 = 24.5 nM) was further evaluated against a HUVEC cell line showing an IC50 of 1.37 μM. Moreover, it showed an indirect anti-angiogenic effect through the suppression of secretion of VEGF and TGF-b1 from prostate cancer cells. Five compounds were selected by the NCI for evaluation of their in vitro anticancer activity against the full NCI panel of cell lines at 10 μM. Compounds 6e and 6f were further selected for 5-dose testing. Compound 6e exerted nanomolar GI50 values against several cell lines: CCRF-CEM (901 nM), MOLT-4 (525 nM) and CAKI-1 (992 nM) and one digit micromolar activity against the rest of the cell lines ranging from 1.05 μM to 2.41 μM. Compound 6f showed one digit micromolar activity against the whole panel of cell lines ranging from 1.55 μM to 7.4 μM. A molecular docking study was employed to investigate the predicted binding mode of the target compounds with VEGFR-2, using Autodock software. Furthermore, MD simulation was implemented for compounds 6i and 10c for further validation and rationalization of their binding mode.

In our attempt to discover effective anticancer agents, three series of novel quinazoline-based compounds have been designed, synthesized and tested as VEGFR-2 inhibitors. Five quinazoline −2-carboxamide derivatives (5d, 5e, 5 h, 5i, 5j) revealed potent nanomolar VEGFR-2 inhibition with IC50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of the reference drug sorafenib (IC50 78.9 nM). Additionally, the quinazoline 2-carboxylate derivative bearing a fluorine substituent in middle ring (7a) showed IC50 values of 14.8 nM. Most of the new synthesized compounds are examined on NCI sixty cell lines of human cancer cells. Furthermore, molecular modeling study was administered to realize any clarification of the binding mode in the inactive VEGFR-2 conformation that demonstrates compatible binding modes similar to those of sorafenib and regorafenib. Finally, several ADME descriptors were calculated through a predictive kinetic study.

Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs) , this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 µM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 µM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.