Hybrid Drugs Research Articles

A prodrug of 3-(ferrocenylaminocarbonyloxymethyl)phenol activated by reactive oxygen species in cancer cells

Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.

Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules.

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin‐based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin‐resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8‐amino‐ or 8‐hydroxyquinoline entity covalently bound to a 1,4‐naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50=622 nm on an artemisinin‐resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents.

Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.

Discovery of Anticancer Hybrid Molecules by Supervised Machine Learning Models and in Vitro Validation in Drug Resistant Chronic Myeloid Leukemia Cells.

The concept of hybrid drugs for targeting multiple aberrant pathways of cancer, by combining the key pharmacophores of clinically approved single-targeted drugs, has emerged as a promising approach for overcoming drug-resistance. Here, we report the design of unique hybrid molecules by combining the two pharmacophores of clinically approved BCR-ABL inhibitor (ponatinib) and HDAC inhibitor (vorinostat) and results of in vitro studies in drug-resistant CML cells. Robust 2D-QSAR and 3D-pharmacophore machine learning supervised models were developed for virtual screening of the hybrid molecules based on their predicted BCR-ABL and HDAC inhibitory activity. The developed 2D-QSAR model showed five information rich molecular descriptors while the 3D-pharmacophore model of BCR-ABL showed five different chemical features (hydrogen bond acceptor, donor, hydrophobic group, positive ion group, and aromatic rings) and the HDAC model showed four different chemical features (hydrogen bond acceptor, donor, positive ion group, and aromatic rings) for potent BCR-ABL and HDAC inhibition. Virtual screening of the 16 designed hybrid molecules identified FP7 and FP10 with better potential of inhibitory activity. FP7 was the most effective molecule with predicted IC50 using the BCR-ABL based 2D-QSAR model of 0.005 μM and that of the HDAC model of 0.153 μM, and that using the BCR-ABL based 3D-pharmacophore model was 0.02 μM and that with HDAC model was 0.014 μM. In vitro study (dose-response relationship) of FP7 in wild type and imatinib-resistant CML cell lines harboring Thr315Ile or Tyr253His mutations showed growth inhibitory IC50 values of 0.000 16, 0.0039, and 0.01 μM, respectively. This molecule also showed better biocompatibility when tested in whole blood and in PBMCs as compared to ponatinib or vorinostat.

Assisting Multitargeted Ligand Affinity Prediction of Receptor Tyrosine Kinases Associated Nonsmall Cell Lung Cancer Treatment with Multitasking Principal Neighborhood Aggregation.

A multitargeted therapeutic approach with hybrid drugs is a promising strategy to enhance anticancer efficiency and overcome drug resistance in nonsmall cell lung cancer (NSCLC) treatment. Estimating affinities of small molecules against targets of interest typically proceeds as a preliminary action for recent drug discovery in the pharmaceutical industry. In this investigation, we employed machine learning models to provide a computationally affordable means for computer-aided screening to accelerate the discovery of potential drug compounds. In particular, we introduced a quantitative structure–activity-relationship (QSAR)-based multitask learning model to facilitate an in silico screening system of multitargeted drug development. Our method combines a recently developed graph-based neural network architecture, principal neighborhood aggregation (PNA), with a descriptor-based deep neural network supporting synergistic utilization of molecular graph and fingerprint features. The model was generated by more than ten-thousands affinity-reported ligands of seven crucial receptor tyrosine kinases in NSCLC from two public data sources. As a result, our multitask model demonstrated better performance than all other benchmark models, as well as achieving satisfying predictive ability regarding applicable QSAR criteria for most tasks within the model’s applicability. Since our model could potentially be a screening tool for practical use, we have provided a model implementation platform with a tutorial that is freely accessible hence, advising the first move in a long journey of cancer drug development.

Radical Releasing Anti-tuberculosis Agents and the Treatment of Mycobacterial Tuberculosis Infections - An Overview.

The treatment and management of tuberculosis (TB) is a major global concern. Approved drugs for the treatment of TB, to date, have displayed various modes of action which can be grouped into radical releasing and non-radical releasing anti-TB agents. Radical releasing agents are of special interest because they diffuse directly into the mycobacterium cell wall, interact with the host cell DNA, causing DNA strand breakages and fatal destabilization of the DNA helix inhibiting nucleic acid synthase. As a therapeutic agent with the aforementioned activity, nitroimidazoles and most especially bicyclic nitroimidazoles are currently in clinical use for the treatment of tuberculosis. However, the approved drugs, pretomanid (PR) and delamanid (DE) are limited in their nitric oxide radical (NO•) releasing abilities to cause effective bactericidity. It is believed that their bactericidal activity can be improved by harnessing alternative strategies to increase NO• release. The last decade has witnessed the strategic inclusion of NO-donors into native drugs to improve their activities and/or reverse resistance. The rationale behind this strategy is the targeting of NO• release at specific therapeutic sites. This review, therefore, aims to highlight various radical releasing agents that may be effective in the treatment of TB. The review also investigates various structural modifications to PR and DE and suggests alternative strategies to improve NO•release as well as some applications where NO-donor hybrid drugs have been used with good therapeutic effect.

Acridine–O6-benzylguanine hybrids: Synthesis, DNA binding, MGMT inhibition and antiproliferative activity

O6-Methylguanine-DNA-methyltransferase (MGMT) is a key DNA repair enzyme involved in chemoresistance to DNA-alkylating anti-cancer drugs such as Temozolomide (TMZ) through direct repair of drug-induced O6-methylguanine residues in DNA. MGMT substrate analogues, such as O6-benzylguanine (BG), efficiently inactivate MGMT in vitro and in cells; however, these drugs failed to reach the clinic due to adverse side effects. Here, we designed hybrid drugs combining a BG residue covalently linked to a DNA-interacting moiety (6-chloro-2-methoxy-9-aminoacridine). Specifically, two series of hybrids, encompassing three compounds each, were obtained by varying the position of the attachment point of BG (N9 of guanine vs. the benzyl group) and the length and nature of the linker. UV/vis absorption and fluorescence data indicate that all six hybrids adopt an intramolecularly stacked conformation in aqueous solutions in a wide range of temperatures. All hybrids interact with double-stranded DNA, as clearly evidenced by spectrophotometric titrations, without intercalation of the acridine ring and do not induce thermal stabilization of the duplex. All hybrids, as well as the reference DNA intercalator (6-chloro-2-methoxy-9-aminoacridine 8), irreversibly inhibit MGMT in vitro with variable efficiency, comparable to that of BG. In a multidrug-resistant glioblastoma cell line T98G, benzyl-linked hybrids 7a–c and the N9-linked hybrid 19b are moderately cytotoxic (GI50 ≥ 15 μM after 96 h), while N9-linked hybrids 19a and 19c are strongly cytotoxic (GI50 = 1–2 μM), similarly to acridine 8 (GI50 = 0.6 μM). Among all compounds, hybrids 19a and 19c, similarly to BG, display synergic cytotoxic effect upon co-treatment with subtoxic doses of TMZ, with combination index (CI) values as low as 0.2–0.3. In agreement with in vitro results, compound 19a inactivates cellular MGMT but, unlike BG, does not induce significant levels of DNA damage, either alone or in combination with TMZ, as indicated by the results of γH2AX immunostaining experiments. Instead, and unlike BG, compound 19a alone induces significant apoptosis of T98G cells, which is not further increased in a combination with TMZ. These results indicate that molecular mechanisms underlying the cytotoxicity of 19a and its combination with TMZ are distinct from that of BG. The strongly synergic properties of this combination represent an interesting therapeutic opportunity in treating TMZ-resistant cancers.

A Study on Leukemic and Non-small Cell Lung Cancer Efficacy of Novel Isoxazoles Synthesized by Microwave Irradiation

Background: The era of drug discovery suggested the designing of “hybrid drugs,” which acquired recognition in the field of medicinal chemistry due to its influential role in preserving different health challenges. Objective: A new series of chalcone derivatives 4a-4i, bearing isoxazole moieties, were designed and synthesized with microwave irradiation, which were biologically evaluated for their activity on NCI- 60 cell-lines to check efficacy in anti-cytotoxic effect. Methods: The required diverse acetophenone molecule was prepared by chloro-amine coupling using lansoprazole (lanso chloro) drug intermediate, i.e., 4-(2,2,2-trifluoroethoxy)-2-(chloromethyl)-3- methylpyridine engaged in the reaction with various aryl aldehydes (2a-2i) in the primary media gave fluoro contained chalcone (3a-3i). The desired isoxazoles (4a-4i) were synthesized by MW (microwave irradiation) based reaction using hydroxylamine for cyclization purposes. Results: The espoused scheme resulted in good yields of a new set of isoxazole-chalcone conjugates with potent cytotoxic activity, which were found in compounds 4h and 4i against the Leukemia RPMI-8226 (With GI50 Values ≈ -10 μg/ml) cancer cell line and the Non-Small Cell Lung Cancer HOP-92 (With GI50 Values ≈ -25 μg/ml) cancer cell line. Conclusion: The optimization of the reaction indicated that the MW based reaction progress was an efficient and time-saving process for the course of isoxazole synthesis. An anticancer study shows that compounds 4h demonstrated significant anticancer activity.

A feasible strategy of fabricating hybrid drugs co-loaded polymer-lipid nanoparticles for the treatment of nasopharyngeal cancer therapy

Effective novel therapies are required for nasopharyngeal cancers since nasopharyngeal patients are dysfunctional, and treatment remains a significant challenge. Here, a co-loading core-shell structured lipid-polymeric hybrids nanoparticles with gefitinib (GEF) and apatinib (APT) was established (GEF-APT-LPHNs). The LPHNs size, polydispersive index (PDI), zeta potential, and drug release properties were effectively investigated. The in vitro proliferation assay and cellular uptake displayed superior activity against the CNE2 and SUNE1 cells. Further, the morphological features of the CNE2 and SUNE1 cells were established by the dual staining method and nuclear damage staining strategy. Additionally, we evaluated an in vitro assay to assess the hemolytic properties of nanoparticles and discuss with the experiment the observed nanointerference. To prevent misleading effects from nanoparticles, we are proposing alternate approaches, debating the possible importance of nanoparticles in vitro systems.

A feasible strategy of fabricating hybrid drugs encapsulated polymeric nanoparticles for the treatment of gastric cancer therapy

Chemotherapy of hybrid-drugs has become one of the widely used therapies for the prevention of cancers with promising clinical results. This study aimed to create compostable polymeric nanoparticles (PPNPs) for the codelivery of capsaicin (CAPS) and biotin (BT) and to examine the anticancer activity of the drug delivery mechanism (CAPS/BT@PPNPs) against in vitro and in vivo gastric cancer cells. Because of the insufficiency of double antitumor drugs BT and CAPS compressed in polymer-based bio-degradable nanoparticles, the encapsulation of BT and CAPS antitumor drugs co-loaded with polyethylene glycol and polylactidecoglycolide nanoparticles (PPNPs) is effective. Transmission electron microscopy (TEM) was utilized to investigate the structure of BT@PPNPs, CAPS@PPNPs, and BT/CAPS@PPNPs, as well as their shape and size. Human gastric carcinoma cell lines, such as SGC-791 and NCI-N87, were also induced to apoptosis in vitro by BT/CAPS@PPNPs. Morphologies and cell death were observed using bio-chemical staining methods, AO/EB (acridine orange/ethidium bromide) and Hoechst. Flow cytometry in dual staining was also used to confirm the mechanistic investigations of apoptosis. Overall, this dual drug delivery strategy suggests that BT/CAPS@PPNPs could be used as a new method to increase the efficacy of gastric therapeutics.

Hybrid Drugs-A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores.

Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges.

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

Multi-Target Drug Candidates for Multifactorial Alzheimer's Disease: AChE and NMDAR as Molecular Targets.

Alzheimer's disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer's symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

Chemical Synthesis, Efficacy, and Safety of Antimalarial Hybrid Drug Comprising of Sarcosine and Aniline Pharmacophores as Scaffolds.

Malaria is a disease caused by protozoans transmitted to humans by infected female Anopheles mosquitoes. According to the WHO report of 2015, there were 214 million cases of malaria with 438,000 deaths worldwide. Ninety percent of world's malaria cases occur in Africa, where the disease is recognized as a serious impediment to economic and social development. Despite advancement in malaria research, the disease continues to be a global problem, especially in developing countries. Currently, there is no effective vaccine for malaria control. In addition, although there are effective drugs for treatment of malaria, this could be lost to the drug resistance in different Plasmodium species. The most lethal form is caused by P. falciparum which has developed resistance to many chemotherapeutic agents and possibly to the current drugs of choice. Reducing the impact of malaria is a key to achieving the sustainable development goals which are geared toward combating the disease. Covalent bitherapy is a rational and logical way of drug design which entails joining a couple of molecules with individual intrinsic action into a unique agent, hence packaging dual activity into one hybrid. This suggests the need to develop new antimalarial drugs that are effective against malaria parasites based on the new mode of action, molecular targets, and chemical structures. In silico studies have shown that sarcosine is able to bind to unique plasmodia proteins (P. falciparum ATCase), whereas aniline can be a ligand to target protein (enoyl acyl carrier protein reductase), hence suppressing the progression of the disease. The main objective of this study was to synthesize and determine the efficacy and safety of antiplasmodial hybrid drug comprising the sarcosine and aniline derivative for management of plasmodial infections. The hybrid drug was synthesized by adding thionyl chloride to sarcosine to form acyl chloride which was then added to aniline to form sarcosine-aniline hybrid molecule. The IC50 of sarcosine-aniline hybrid was 44.80 ± 4.70 ng/ml compared with that of aniline derivative which was 22.86 ± 1.26 ng/ml. The IC50 of control drugs was 2.63 ± 0.38 ng/ml and 5.69 ± 0.39 ng/ml for artesunate and chloroquine, respectively. There was a significant difference between IC50 of sarcosine-aniline hybrid and aniline derivative (p < 0.05). There was also a significant difference between sarcosine-aniline hybrid and standard drugs used to treat malaria including artesunate and chloroquine (p < 0.05). The ED50 of sarcosine-aniline hybrid drug was 6.49 mg/kg compared with that of aniline derivative which was 3.61 mg/kg. The ED50 of control drugs was 3.56 mg/kg, 2.94 mg/kg, and 1.78 mg/kg for artesunate-aniline hybrid, artesunate, and chloroquine, respectively. There was a significant difference (p < 0.05) between ED50 of sarcosine-aniline hybrid and both controls such as aniline derivative, artesunate, artesunate-aniline hybrid, and chloroquine. Cytotoxicity results revealed that sarcosine-aniline hybrid was safe to vero cells with a CC50 of 50.18 ± 3.53 μg/ml. Sarcosine-aniline hybrid was significantly less toxic compared with artesunate, chloroquine, and doxorubicin. Sarcosine-aniline hybrid was efficacious and safe to mice. Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation.

Synthesis of novel naphthalene-heterocycle hybrids with potent antitumor, anti-inflammatory and antituberculosis activities.

Multitarget-directed drugs (hybrid drugs) constitute an efficient avenue for the treatment of multifactorial diseases. In this work, novel naphthalene hybrids with different heterocyclic scaffolds such as nicotinonitrile, pyran, pyranopyrazole, pyrazole, pyrazolopyridine, and azepine were efficiently synthesized via tandem reactions of 3-formyl-4H-benzo[h]chromen-4-one 1 with different nucleophilic reagents. Analysis of these hybrids using PASS online software indicated different predicted biological activities such as anticancer, antimicrobial, antiviral, antiprotozoal, anti-inflammatory, etc. By focusing on antitumor, anti-inflammatory, and antituberculosis activities, many compounds revealed remarkable activities. While 3c, 3e, and 3h were more potent than doxorubicin in the case of HepG-2 cell lines, 3a–e, 3i, 6, 8, 10, 11, and 12b were more potent in the case of MCF-7. Moreover, compounds 3c, 3h, 8, 10, 3d, and 12b manifested superior activity and COX-2 selectivity to the reference anti-inflammatory Celecoxib. Regarding antituberculosis activity, 3c, 3d, and 3i were found to be the most promising with MIC less than 1 μg mL−1. The molecular docking studies showed strong polar and hydrophobic interactions with the novel naphthalene-heterocycle hybrids that were compatible with experimental evaluations to a great extent.

Enhancement of Antibiotics activity by microbially synthesized silver nanoparticles

Biological synthesis of nanoparticles is a promising approach that is comparatively inexpensive and eco-friendly. Among various microorganisms, actinobacteria have been found to be efficient in the synthesis of nanomaterials. In thisstudy, extracellular biosynthesis of silver nanoparticles (Ag-NPs) was investigated by mixing silver nitrate with culture filtrate of Streptomyces rochei strain MFA-37.The biosynthesized Ag-NPs were characterized by UV–Vis spectrophotometric analysis, and showed a peak of absorbance at 440 nm. Fourier transform infrared (FTIR) analysis showed amines and amides that are responsible for the stabilization of Ag-NPs. The morphology and size of nanoparticles were determined using high-resolution transmission electron microscopy, XRD and DLS techniques which indicated well dispersed, spherical Ag-NPs sized 2–20 nm, and the zeta potential of AgNPs reached -20.5 mV. Enhancement of antibacterial activity of fourteen antibiotics was conducted by combining antibiotics with synthesized AgNPs. The synergistic activities of AgNPs combination with antibiotics were determined using disc diffusion against two multi-drug resistant Staphylococcus aureus SA-185 and SA-325 recovered from Libya. The highest synergistic effects were 6.11 and 6.37 folds for Penicillin followed by 6.11 and 4.44 folds for Ciprofloxacin and 6.11 and 3.69 folds for Erythromycin for MRSA-185 and MRSA-325 , respectively. This activity of AgNPs and antibiotics could be valuable for the manufacture of hybrid drugs to kill or inhibit the MRSA infection especially in case of superficial injuries.

Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment.

Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors' role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.

Quinoline-Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action.

The role of autophagy in cancer is often complex, ranging from tumor‐promoting to ‐suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo‐[3‐(η 6‐p‐cymene)‐1‐(quinolin‐8‐yl‐acetate)‐3,1,2‐RuC2B9H10] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor‐promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy‐prone glioblastomas.

Anti-Inflammatory and Anti-Hyperuricemic Functions of Two Synthetic Hybrid Drugs with Dual Biological Active Sites.

The present study aimed to test the anti-inflammatory and xanthine oxidase inhibitory activities of two synthesized molecules and compare them to routinely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and the serum urate-lowering drug, allopurinol. The anti-inflammatory effects of the designed compounds (A and B) were evaluated in carrageenan (CAR)-induced paw edema in mice. The levels of nitric oxide and myeloperoxidase activity were measured in paw skin using biochemical methods. Additionally, prostaglandin E2 (PGE2), C-reactive protein (CRP), cyclooxygenase-2 (Cox-2), tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-2 and IL-10, and monocyte chemoattractant protein-1 (MCP1) were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of inflammation-related genes was confirmed by real-time qPCR. The expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were estimated using immunohistochemistry, and xanthine oxidase inhibitory activity was evaluated using an in vitro assay. The results revealed that compounds A and B decreased inflammation, as was observed by a reduction in the elevation of all the tested markers. In addition, the tested compounds markedly decreased paw swelling, mobilization of inflammatory cells, iNOS-, and NF-κB-immunoreactive cells in a mouse model of paw edema. Interestingly, both compounds were potent xanthine oxidase inhibitors as well as Cox inhibitors with higher activity in favor of compound B providing potential dual acting series of anti-hyperuricemic and anti-inflammatory therapeutic agents.