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A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC 50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC 50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC 50 = 0.205 μM) and MMP-13 (IC 50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.

Non-small cell lung cancer (NSCLC) continues to be a leading cause of cancer death. Its fatality is associated with angiogenesis and metastasis. While VEGFR inhibitors are expected to be the central pillar for halting lung cancer, several clinical reports declared their subpar activities as monotherapy. These results directed combination studies of VEGFR inhibitors, especially sorafenib (Nexavar®), with various chemotherapeutic agents. Matrix metalloproteinase (MMP) inhibitors are seldom utilized in such combinations despite the expected complementary therapeutic outcome. This could be attributed to the clinical unsuitability of MMP inhibitors from the hydroxamate family. Herein, we report new non-hydroxamate s-triazinedione-based inhibitors of MMP-9 (6b; IC 50  = 0.112 μM), and MMP-10 (6e; IC 50  = 0.076 μM) surpassing the hydroxamate inhibitor NNGH for chemosensitization of NSCLC to sorafenib. MMPs inhibition profiling of the hits revealed MMP-9 over -2 and MMP-10 over -13 selectivity. 6b and 6e were potent (IC 50  = 0.139 and 0.136 µM), safe (SI up to 6.77) and superior to sorafenib (IC 50  = 0.506 µM, SI = 6.27) against A549 cells. When combined with sorafenib, the studied MMP inhibitors enhanced its cytotoxic efficacy up to 26 folds as confirmed by CI and DRI values for 6b (CI = 0.160 and DRI = 22.175) and 6e (CI = 0.096 and DRI = 29.060). 6b and 6e exerted anti-invasive activities in A549 cells as single agents (22.66 and 39.67 %) and in sorafenib combinations (29.96 and 91.83 %) compared to untreated control. Both compounds downregulated VEGF in A549 cells by approximately 70 % when combined with sorafenib, highlighting enhanced anti-angiogenic activities. Collectively, combinations of 6b and 6e with sorafenib demonstrated synergistic NSCLC cytotoxicity with pronounced anti-invasive and anti-angiogenic activities introducing a promising start point for preclinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the therapeutic outcome based on mechanistic ferroptosis studies highlighting the interplay with MMPs, especially MMP-13 associated with CRC metastasis and poor prognosis. Herein, we report new hybrid triazines capable of simultaneous MMP-10/13 inhibition and ferroptosis induction bridging the gap between their anticancer potentials. The MMP-10/13 inhibitory component of the scaffold was based on the non-hydroxamate model inhibitors. s-Triazine was rationalized as the core inspired by altretamine, an FDA-approved ferroptosis inducer. The ferroptosis pharmacophores were then installed as Michael acceptors via triazole-based spacers. The electrophilic reactivity was tuned by incorporating cyano and/or substituted phenyl groups influencing their electronic and steric properties and enriching the SAR study. Initial screening revealed the outstanding cytotoxicity profiles of the nitrophenyl-tethered chalcone 5e and the cyanoacrylohydrazides bearing p-fluorophenyl 9b and p-bromophenyl 9d appendages. 9b and 9d surpassed NNGH against MMP-10 and -13, especially 9d (IC 50  = 0.16 μM). Ferroptosis studies proved that 9d depleted GSH in HCT-116 cells by a relative fold decrement of 0.81 with modest direct GPX4 inhibition, thus inducing lipid peroxidation, the hallmark of ferroptosis, by 1.32 relative fold increment. Docking presumed that 9d could bind to the MMP-10 S1' pocket and active site His221, extend through the MMP-13 hydrophobic pocket, and interact covalently with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles was 7.5 folds more cytotoxic than its free precursor against HCT-116 cells. The complex-induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, consequently triggering lipid peroxidation and ferroptosis by a 3.94 relative fold increment. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: CLA (conjugated linoleic acid)-mediated activation of the schistosome tegument-associated sphingomyelinase and consequent disruption of the outer membrane might allow host antibodies to access the apical membrane antigens. Here, we investigated a novel approach to enhance specific antibody delivery to concealed surface membrane antigens of Schistosoma mansoni utilising antibody-conjugated-CLA nanomicelle technology., Methodology/principal Findings: We invented and characterised an amphiphilic CLA-loaded whey protein co-polymer (CLA-W) as an IV injectable protein nanocarrier. Rabbit anti-Schistosoma mansoni infection (anti-SmI) and anti-Schistosoma mansoni alkaline phosphatase specific IgG antibodies were purified from rabbit sera and conjugated to the surface of CLA-W co-polymer to form antibody-conjugated-CLA-W nanomicelles (Ab-CLA-W). We investigated the schistosomicidal effects of CLA-W and Ab-CLA-W in a mouse model of Schistosoma mansoni against early and late stages of infection. Results showed that conjugation of nanomicelles with antibodies, namely anti-SmI, significantly enhanced the micelles' schistosomicidal and anti-pathology activities at both the schistosomula and adult worm stages of the infection resulting in 64.6%-89.9% reductions in worm number; 72.5-94% and 66.4-85.2% reductions in hepatic eggs and granulomas, respectively. Treatment induced overall improvement in liver histopathology, reducing granuloma size and fibrosis and significantly affecting egg viability. Indirect immunofluorescence confirmed CLA-W-mediated antigen exposure on the worm surface. Electron microscopy revealed extensive ultrastructural damage in worm tegument induced by anti-SmI-CLA-W., Conclusion/significance: The novel antibody-targeted nano-sized CLA delivery system offers great promise for treatment of Schistosoma mansoni infection and control of its transmission. Our in vivo observations confirm an immune-mediated enhanced effect of the schistosomicidal action of CLA and hints at the prospect of nanotechnology-based immunotherapy, not only for schistosomiasis, but also for other parasitic infections in which chemotherapy has been shown to be immune-dependent. The results propose that the immunodominant reactivity of the anti-SmI serum, Schistosoma mansoni fructose biphosphate aldolase, SmFBPA, merits serious attention as a therapeutic and vaccine candidate., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Amer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bacterioruberin and its rare glycosylated derivatives are produced by Arthrobacter agilis as an adaptation strategy to low temperature conditions. The high antioxidant properties of bacterioruberin held great promise for different future applications like the pharmaceutical and food industries. Microbial production of bacterioruberin via a cost-effective medium will help increase its commercial availability and industrial use. The presented study aims to optimize the production of the rare C 50 carotenoid bacterioruberin and its derivatives from the psychotrophic bacteria Arthrobacter agilis NP20 strain on a whey-based medium as a cost effective and readily available nutritious substrate. The aim of the study is extended to assess the efficiency of whey treatment in terms of estimating total nitrogen content in treated and untreated whey samples. The significance of medium ingredients on process outcome was first tested individually; then the most promising factors were further optimized using Box Behnken design (BBD). The produced carotenoids were characterized using UV-visible spectroscopy, FTIR spectroscopy, HPLC-DAD chromatography and HPLC-APCI-MS spectrometry. The maximum pigment yield (5.13 mg/L) was achieved after a 72-h incubation period on a core medium composed of 96% sweet whey supplemented with 0.46% MgSO 4 & 0.5% yeast extract and inoculated with 6% (v/v) of a 24 h pre-culture (10 9  CFU/mL). The cost of the formulated medium was 1.58 $/L compared with 30.1 $/L of Bacto marine broth medium. The extracted carotenoids were identified as bacterioruberin, bis-anhydrobacteriouberin, mono anhydrobacterioruberin, and glycosylated bacterioruberin. The presented work illustrates the possibility of producing bacterioruberin carotenoid from Arthrobacter agilis through a cost-effective and eco-friendly approach using cheese whey-based medium., (© 2023. The Author(s).)

Aim: Despite extensive progress in the field of cancer nanotheranostics, clinical development of biocompatible theranostic nanomedicine remains a formidable challenge. Herein, we engineered biocompatible silk-sericin-tagged inorganic nanohybrids for efficient treatment and imaging of cancer cells. The developed nanocarriers are anticipated to overcome the premature release of the chemotherapeutic drug pemetrexed (PMX), enhance the colloidal stability of layered double hydroxides (LDHs), and maintain the luminescence properties of ZnO quantum dots (QDs). Materials and Methods : PMX-intercalated LDHs were modified with sericin and coupled to ZnO QDs for therapy and imaging of breast cancer cells. Results : The optimized nanomedicine demonstrated a sustained release profile of PMX, and high cytotoxicity against MDA-MB-231 cells compared to free PMX. In addition, high cellular uptake of the engineered nanocarriers into MDA-MB-231 breast cancer cells was accomplished. Conclusions : Conclusively, the LDH-sericin nanohybrids loaded with PMX and conjugated to ZnO QDs offered a promising cancer theranostic nanomedicine., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

While breast cancer remains a global health concern, the elaboration of rationally designed drug combinations coupled with advanced biocompatible delivery systems offers new promising treatment venues. Herein, we repurposed rosuvastatin (RST) based on its selective tumor apoptotic effect and combined it with the antimetabolite pemetrexed (PMT) and the tumor-sensitizing polyphenol honokiol (HK). This synergistic three-drug combination was incorporated into protein polysaccharide nanohybrids fabricated by utilizing sodium alginate (ALG) and lactoferrin (LF), inspired by the stealth property of the former and the cancer cell targeting capability of the latter. ALG was conjugated to PMT and then coupled with LF which was conjugated to RST, forming core shell nanohybrids into which HK was physically loaded, followed by cross linking using genipin. The crosslinked HK-loaded PMT-ALG/LF-RST nanohybrids exhibited a fair drug loading of 7.86, 5.24 and 6.11% for RST, PMT and HK, respectively. It demonstrated an eight-fold decrease in the IC50 compared to the free drug combination, in addition to showing an enhanced cellular uptake by MCF-7 cells. The in vivo antitumor efficacy in a breast cancer-bearing mouse model confirmed the superiority of the triple cocktail-loaded nanohybrids. Conclusively, our rationally designed triple drug-loaded protein/polysaccharide nanohybrids offer a promising, biocompatible approach for an effective breast tumor suppression.

The current treatment protocols for breast cancer have shifted from single agent therapies to combinatorial approaches that offer synergistic efficacies and reduced side effects. Self-assembled nanogels comprising natural polysaccharides and functional proteins provide an intelligent platform for the targeted co-delivery of therapeutic molecules. Herein, we report the fabrication of self-assembled nanogels utilizing hydrophilic biocompatible proteins, lactoferrin (Lf), and polysaccharide carboxy methyl cellulose (CMC), for the combined delivery of the antimetabolite pemetrexed (PMT) and the herbal polyphenol honokiol (HK). PMT was conjugated to LF via an amide bond. The conjugate was then electrostatically assembled into CMC under optimized conditions to form nanogels (Lf-CMC NGs). An inclusion complex of HK with hydroxypropyl-β-cyclodextrin was then encapsulated in the prepared Lf-CMC NGs with an entrapment efficiency of 66.67%. The dual drug-loaded cross-linked Lf-CMC NGs exhibited a particle size of 193.4 nm and zeta potential of - 34.5 mV and showed a sustained release profile for both drugs. PMT/HK-loaded Lf-CMC NGs were successfully taken up by MDA-MB-231 breast cancer cells and demonstrated superior in vitro cytotoxicity, as elucidated by a low combination index value (CI=0.17) and a higher dose reduction index (DRI) compared to those of the free drugs. An in vivo antitumor study using an Ehrlich ascites tumor (EAT) mouse model revealed the robust efficacy of PMT/HK-loaded Lf-CMC NGs in inhibiting tumor growth, which was ascribed to the reduced expression level of VEGF-1, elevated protein expression level of caspase-3, and suppressed Ki-67 protein level in the tumor tissue (P ˂0.05). In conclusion, our green fabricated self-assembled dual-loaded nanogels offer a promising biocompatible strategy for targeted combinatorial breast cancer therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is one of the most devastating diseases worldwide. Immunotherapeutic agents for CRC treatment have shown limited efficacy due to the immunosuppressive tumor microenvironment (TME). In this context, various types of nanoparticles (NPs) have been used to reverse the immunosuppressive TME, potentiate the effect of immunotherapeutic agents and reduce their systemic side effects. Many advantages could be offered by NPs, related to drug-loading efficiency, particle size and others that can potentially aid the delivery of immunotherapeutic agents. The recent research on how nano-based immunotherapy can remodel the immunosuppressive TME of CRC and hence boost the antitumor immune response, as well as the challenges that face clinical translation of NPs and future perspectives, are summarized in this review article.

Off-target side effects are major challenges hindering the clinical success of matrix metalloproteinase (MMP) inhibitors. Various targeting strategies revitalized MMP research to eliminate this drawback. Herein, we developed s -triazine-based dendrimeric architecture not only amenable to tumor targeting but also decorated with pharmacophoric entities to endow MMP-9 inhibition for halting cancer progression. The design rationale utilized hydrazide branching chains as well as carboxylic and hydroxamic acid termini as Zn-binding groups to confer substantial MMP inhibitory potential. The carboxylic acids are tetherable to tumor targeting ligands and other cargo payloads as synergistic drugs via biodegradable linkages. The synthesized series were screened for cytotoxicity against normal fibroblasts (Wi-38) and two selected cancers (MDA-MB 231 and Caco-2) via MTT assay. The most active hexacarboxylic acid dendrimer 8a was more potent and safer than Dox against MDA-MB 231 and Caco-2 cells. It intrinsically inhibited MMP-9 with selectivity over MMP-2. Docking simulations demonstrated that the extended carboxylic acid termini of 8a could possibly chelate the active site Zn of MMP-9 and form hydrogen-bonding interactions with the ligand essential backbone Tyr423. In addition, it suppressed the correlated oncogenic mediators VEGF and cyclin D, upregulated p21 expression, induced apoptosis (>75%), and inhibited the tumor cell migration (∼84%) in the treated cancer cells. Thus, up to our knowledge, it is the first triazine-based MMP-9 inhibitor dendrimer endowed with VEGF suppression potential that can be employed as a bioactive carrier., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Cold active esterases have gained great interest in several industries. The recently determined structure of a family IV cold active esterase (EstN7) from Bacillus cohnii strain N1 was used to expand its substrate range and to probe its commercially valuable substrates. Database mining suggested that triacetin was a potential commercially valuable substrate for EstN7, which was subsequently proved experimentally with the final product being a single isomeric product, 1,2-glyceryl diacetate. Enzyme kinetics revealed that EstN7's activity is restricted to C2 and C4 substrates due to a plug at the end of the acyl binding pocket that blocks access to a buried water-filled cavity. Residues M187, N211 and W206 were identified as key plug forming residues. N211A stabilised EstN7 allowing incorporation of the destabilising M187A mutation. The M187A-N211A double mutant had the broadest substrate range, capable of hydrolysing a C8 substrate. W206A did not appear to have any significant effect on substrate range either alone or when combined with the double mutant. Thus, the enzyme kinetics and engineering together with a recently determined structure of EstN7 provide new insights into substrate specificity and the role of acyl binding pocket plug residues in determining family IV esterase stability and substrate range.

While the treatment regimen of certain types of breast cancer involves a combination of hormonal therapy and chemotherapy, the outcomes are limited due to the difference in the pharmacokinetics of both treatment agents that hinders their simultaneous and selective delivery to the cancer cells. Herein, we report a hybrid carrier system for the simultaneous targeted delivery of aromatase inhibitor exemestane (EXE) and methotrexate (MTX). EXE was physically loaded within liquid crystalline nanoparticles (LCNPs), while MTX was chemically conjugated to lactoferrin (Lf) by carbodiimide reaction. The anionic EXE-loaded LCNPs were then coated by the cationic MTX-Lf conjugate via electrostatic interactions. The Lf-targeted dual drug-loaded LCNPs exhibited a particle size of 143.6 ± 3.24 nm with a polydispersity index of 0.180. It showed excellent drug loading with an EXE encapsulation efficiency of 95% and an MTX conjugation efficiency of 33.33%. EXE and MTX showed synergistic effect against the MCF-7 breast cancer cell line with a combination index (CI) of 0.342. Furthermore, the Lf-targeted dual drug-loaded LCNPs demonstrated superior synergistic cytotoxic activity with a combination index (CI) of 0.242 and a dose reduction index (DRI) of 34.14 and 4.7 for EXE and MTX, respectively. Cellular uptake studies demonstrated higher cellular uptake of Lf-targeted LCNPs into MCF-7 cancer cells than non-targeted LCNPs after 4 and 24 h. Collectively, the targeted dual drug-loaded LCNPs are a promising candidate offering combinational hormonal therapy/chemotherapy for breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mokhtar, Khattab, Elkhodairy, Teleb, Bekhit, Elzoghby and Sallam.)

Histone deacetylase inhibitors (HDACi) are cancer therapeutics that operate at the epigenetic level and which have recently gained wide attention. However, the applications of HDACi are generally hindered by their poor physicochemical characteristics and unfavorable pharmacokinetic profile. Inspired by the approved nanomedicine-based drugs in the market, nanocarriers could provide a resort to circumvent the limitations imposed by HDACi. Enhanced tumor targeting, improved cellular uptake and reduced toxicity are major advantages offered by HDACi-loaded nanoparticles. More importantly, site-specific drug delivery can be achieved via engineered stimuli-responsive nanosystems. In this review we elucidate the anticancer mechanisms of HDACi and their structure-activity relationships, with a special focus on their nanomedicine-based delivery, different drug loading concepts and their implications.

Polymeric nanocapsules are vesicular drug-delivery systems composed of an inner oily reservoir surrounded by polymeric membranes. Nanocapsules have various advantages over other nanovesicular systems such as providing controlled drug release properties. We discuss the recent advances in polymeric shell oily-core nanocapsules, illustrating the different types of polymers used and their implementation. Nanocapsules can be utilized for many purposes, especially encapsulation of highly lipophilic drugs. They have been shown to have variable applications, especially in cancer therapy, due to the ability of the polymeric shell to direct the loaded drugs to their target sites, as well as their high internalization efficacy. Those productive applications guaranteed their high potential as drug-delivery systems. However, their clinical development is still in an early stage.

Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel 'smart' carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel "super intelligent" lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the pursuit of new compounds for co-treatment to enhance the anticancer efficacy of cisplatin against lung adenocarcinoma, a series of chalcone-tethered 1,3,5-triazines was designed and synthesized. MTT assay was used to evaluate the anticancer activity of the combinations in which two hybrids 10 and 12 were found to significantly inhibit A549 cancer cells viability and their IC 50 values were 24.5 and 17 µM, respectively in reference to cisplatin (IC 50  = 21.5 µM). The combined effect of cisplatin with each of 10 and 12 was analyzed according to Chou-Talalay method against both A549 and normal human fibroblast cells. Mechanistic studies employing MALDI-TOF MS and fluorescence spectroscopy using Evagreen probe inferred that 10 and 12 induced DNA double strand breaks in contrast to cisplatin which induces DNA interstrand cross-links. Also, DNA damage kinetics study demonstrated the difference in the rate of DNA damage induced by both 10 and 12 alone and in combination with cisplatin. Further Annexin V-FITC/propidium iodide dual staining assay provided evidence that 10 and 12 induced apoptosis via different pattern to cisplatin and their combination with cisplatin promoted more cells to enter late apoptosis and necrosis. Molecular docking of 10 and 12 in the active pocket of DNA dodecamer displayed their binding modes with higher number of stable hydrogen bond donor as well as π-H interactions in reference to the original ligand., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bacterial nanocellulose (BNC) is a nanofibrillar polymer that possesses unique characteristics such as high chemical purity, mechanical strength, flexibility, and absorbency. In addition, different bacterial strains can form nanocellulose (NC) in multiple shapes and sizes. This study describes the first report of a marine Bacillus strain that is able to synthesize NC. The strain identified as B. velezensis SMR based on 16S rDNA sequencing, produced highly structured NC, as confirmed by X-ray diffraction (XRD) and Scanning Electron Microscopic Analysis (SEM). In Hestrin-Schramm (HS) medium, B. velezensis SMR produced twice the quantity of BNC in comparison to the reference strain, G. xylinus ATCC 10245. The ability of B. velezensis SMR to produce NC using different industrial waste materials as growth media was tested. Growth in Ulva seaweed extract supported a 2.5-fold increase of NC production by B. velezensis SMR and a threefold increase in NC production by G. xylinus ATCC 10245. As proof of principle for the usability of NC from B. velezensis SMR, we successfully fabricated a BNC-based polyvinyl alcohol hydrogel (BNC-PVA) system, a promising material used in different fields of application such as medicine, food, and agriculture.

Herein we report promoted anti-cancer activity via a combination strategy of synergistic chemotherapy/retinoid-based breast cancer therapy with shell-stabilized micellar green nanomedicine. Amphiphilic zein-chondroitin sulfate (ChS)-based copolymeric micelles (PMs) were successfully developed via carbodiimide coupling for concomitant delivery of etoposide (ETP) and all-trans retinoic acid (ATRA) to breast cancer. The micelles exhibited low critical micellar concentration (CMC) of 0.008 mg/mL with high encapsulation efficiencies of ETP and ATRA (61.2 and 84.29%, respectively). Calcium-mediated crosslinking of the anionic ChS micellar shell resulted in prolonged drug release with small micellar size of 222.7 nm. The micelles exhibited augmented internalization into MCF-7 breast cancer cells by virtue of ChS binding affinity to CD44 receptors overexpressed by cancer cells. Consequently, the ETP/ATRA-loaded micelles exhibited synergistic cytotoxicity against breast cancer cells as revealed by their significantly lower IC 50 , combination index (CI), and higherdose reduction index (DRI) in comparison to the free ETP and free ATRA or their combination. Micelles displayed superiority in reducing tumor volume, decreasing proliferation, and promoting necrosis in mice bearing Ehrlich Ascites Tumor (EAT) upon comparison to free ETP and free ATRA or their combination. Overall, the developed green zein-ChS micelles offer a promising platform for tumor-targeted delivery of hydrophobic therapeutic agents., Competing Interests: Declaration of Competing Interest The authors declare no competing financial or non-financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Despite the clinical approval of few nanomedicines for cancer therapy, some drawbacks still impede their improved efficiency including low drug loading, off-target toxicity and development of multi-drug resistance. Herein, lactoferrin (Lf)-coupled mesoporous silica nanoparticles (MSNPs) were developed for combined delivery of the cytotoxic drug pemetrexed (PMT) and the phytomedicine ellagic acid (EA) for synergistic breast cancer therapy. While the hydrophobic EA was physically encapsulated within the pores of MSNPs via the adsorptive properties of MSNPs and the electrostatic interactions between the negatively charged EA and positively charged amino modified MSNs, the highly water soluble PMT was chemically anchored to the Lf shell through chemical conjugation to the surface of lactoferrin coated MSNPs by carbodiimide reaction to avoid pre-mature drug release and systemic toxicity. The dual drug-loaded Lf-MSNPs (284 nm) demonstrated a sequential faster release of EA followed by a sustained release of PMT. The dual drug-loaded Lf-MSNPs exhibited highest cytotoxicity against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells as revealed by the lowest combination index (CI = 0.885) compared to free drugs. The combination index value (< 1) revealed synergy between both loaded drugs. Furthermore, high cellular uptake of the nanocarriers into MCF-7 breast cancer cells was observed via Lf-receptor mediated endocytosis. Altogether, the dual drug-loaded Lf-targeted MSNPs showed to be a promising carrier for breast cancer therapy through triggering different signaling pathways, and hence overcoming the multi-drug resistance and minimizing the systemic toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds against Staphylococcus aureus, Escherichia coli and Candida albicans using the two-fold serial dilution technique and against reference standards Ampicillin for the antibacterial screening and Clotrimazole regarding the antifungal evaluation. The tested compounds showed strong to moderate antibacterial inhibitory action and weak antifungal activity. Compounds 3j and 6b were the most potent antibacterial agents against the tested strains and multi-drug resistant (MDR) clinical isolates of Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA1) with minimal toxicity in comparison to the reference drugs. In silico molecular properties calculations and molecular docking study for 3j and 6b revealed that both compounds could be considered as promising antibacterial DNA gyrase B inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The rationale of this study is to combine the merits of both albumin nanoparticles and quantum dots (QDs) in improved drug tumor accumulation and strong fluorescence imaging capability into one carrier. However, premature drug release from protein nanoparticles and high toxicity of QDs due to heavy metal leakage are among challenging hurdles. Following this platform, we developed cancer nano-theranostics by coupling biocompatible albumin backbone to CdTe QDs and mannose moieties to enhance tumor targeting and reduce QDs toxicity. The chemotherapeutic water soluble drug pemetrexed (PMT) was conjugated via tumor-cleavable bond to the albumin backbone for tumor site-specific release. In combination, the herbal hydrophobic drug resveratrol (RSV) was preformulated as phospholipid complex which enabled its physical encapsulation into albumin nanoparticles., Results: Albumin-QDs theranostics showed enhanced cytotoxicity and internalization into breast cancer cells that could be traced by virtue of their high fluorescence quantum yield and excellent imaging capacity. In vivo, the nanocarriers demonstrated superior anti-tumor effects including reduced tumor volume, increased apoptosis, and inhibited angiogenesis in addition to non-immunogenic response. Moreover, in vivo bioimaging test demonstrated excellent tumor-specific accumulation of targeted nanocarriers via QDs-mediated fluorescence., Conclusion: Mannose-grafted strategy and QD-fluorescence capability were beneficial to deliver albumin nanocarriers to tumor tissues and then to release the anticancer drugs for killing cancer cells as well as enabling tumor imaging facility. Overall, we believe albumin-QDs nanoplatform could be a potential nano-theranostic for bioimaging and targeted breast cancer therapy.

Aim: Monascin and ankaflavin, the major fractions of the fungal-derived monascus yellow pigments, were incorporated with the herbal drug, resveratrol (RSV) within the core of folate-conjugated casein micelles (FA-CAS MCs, F1) for active targeting. PEGylated RSV-phospholipid complex bilayer enveloping casein-loaded micelles (PEGPC-CAS MCs) were also developed as passive-targeted nanosystem., Results: FA- and PEGPC-CAS MCs demonstrated a proper size with monomodal distribution, sustained drug release profiles and good hemocompatibility. The coloaded MCs showed superior cytotoxicity to MCF-7 breast cancer cells compared with free drugs. Both nanosystems exerted excellent in vivo antitumor efficacy in breast cancer bearing mice with PEGylated MCs showing comparable tumor regression to folate-conjugated MCs., Conclusion: Evergreen nanoplatforms coloaded with monascus yellow pigments and RSV were effective for breast cancer treatment.

Aim: Multireservoir nanocarriers were fabricated for delivering antineoplastic drug cocktail from herbal and fungal origin. Monascus yellow pigments (MYPs), monascin and ankaflavin, were isolated from red-mold rice, and incorporated within casein micelles (CAS MCs) along with the herbal drug, resveratrol (RSV). Both drugs (MYPs and RSV) were simultaneously incorporated into the hydrophobic core of CAS MCs. Alternatively, MYPs-loaded CAS MCs were enveloped within RSV-phytosomal bilayer elaborating multireservoir nanocarriers., Results: Cytotoxicity studies confirmed the superiority of multireservoir nanocarriers against MCF-7 breast cancer cells. The in vivo antitumor efficacy was revealed by reduction of the tumor volume and growth biomarkers., Conclusion: Multireservoir CAS nanocarriers for codelivery of both MYPs and RSV may be promising alternative to traditional breast cancer therapy.

Background: Replacement of chloride ions in cyanuric chloride give several variants of 1,3,5-triazine derivatives which were investigated as biologically active small molecules. These compounds exhibit antimalarial, antimicrobial, anti-cancer and anti-viral activities, among other beneficial properties. On the other hand, treatment of bacterial infections remains a challenging therapeutic problem because of the emerging infectious diseases and the increasing number of multidrug-resistant microbial pathogens. As multidrug-resistant bacterial strains proliferate, the necessity for effective therapy has stimulated research into the design and synthesis of novel antimicrobial molecules., Results: 1,3,5-Triazine 4-aminobenzoic acid derivatives were prepared by conventional method or by using microwave irradiation. Using microwave irradiation gave the desired products in less time, good yield and higher purity. Esterification of the 4-aminobenzoic acid moiety afforded methyl ester analogues. The s-triazine derivatives and their methyl ester analogues were fully characterized by FT-IR, NMR ( 1 H-NMR and 13 C-NMR), mass spectra and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activity. Some tested compounds showed promising activity against Staphylococcus aureus and Escherichia coli., Conclusions: Three series of mono-, di- and trisubstituted s-triazine derivatives and their methyl ester analogues were synthesized and fully characterized. All the synthesized compounds were evaluated for their antimicrobial activity. Compounds (10), (16), (25) and (30) have antimicrobial activity against S. aureus comparable to that of ampicillin, while the activity of compound (13) is about 50% of that of ampicillin. Compounds (13) and (14) have antimicrobial activity against E. coli comparable to that of ampicillin, while the activity of compounds (9-12) and (15) is about 50% of that of ampicillin. Furthermore, minimum inhibitory concentrations values for clinical isolates of compounds (10), (13), (14), (16), (25) and (30) were measured. Compounds (10) and (13) were more active against MRSA and E. coli than ampicillin. Invitro cytotoxicity results revealed that compounds (10) and (13) were nontoxic up to 250 µg/mL (with SI = 10) and 125 µg/mL (with SI = 5), respectively. Graphical abstract Three series of mono-, di- and trisubstituted s-triazine derivatives and their methyl ester analogues were synthesized and evaluated for their antimicrobial activity. Several compounds have antimicrobial activity against S. aureus and E. coli comparable to that of ampicillin.

Steviolbioside (Sb) was synthesized from stevioside and characterized by infrared, nuclear magnetic resonance ( 1 H NMR and 13 C NMR) spectroscopy. The purity melting point, solubility, acute toxicity, heat stability and sensory properties of Sb were evaluated. Physico-chemical and sensory properties of low calorie fruit drinks and shortened cake prepared by replacing sugar with Sb were evaluated. Sb was stable in neutral or acidic aqueous solutions maintained at 100 °C for 2 h. The sweetness intensity rate of Sb was found to be about 44 and 18.51 times sweeter than 0.5% and 10% sucrose solution, respectively. Sb solutions had sweet taste without bitterness compared to stevioside. No significant differences between the organoleptic properties of cakes prepared using sugar and those prepared replacing sugar with 50% Sb were observed. All drinks replacing sugar with Sb at 66% level had the highest overall acceptability scores comparable to those prepared using sugar alone.

2-MeTHF and CPME were evaluated as greener alternatives for the most employed solvents in peptide synthesis. The ability of these solvents to dissolve amino acid derivatives and a range of coupling reagents were evaluated as well as the swelling of polystyrene and polyethylene glycol resins. In addition, racemization and coupling efficiencies were also determined. We concluded that the use of 2-MeTHF with combination of DIC/OxymaPure gave the lowest racemization level during stepwise synthesis of Z-Phg-Pro-NH2 and the highest purity during SPPS of Aib-enkephalin pentapeptide (H-Tyr-Aib-Aib-Phe-Leu-NH2).

Three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.

Eight novel N'-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a-h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 μM) as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32-50 μM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC50 value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.

Here we describe two novel uronium salts, TOMBU and COMBU, derived from the recently described Oxyma-B for use in peptide bond synthesis. These coupling reagents are more stable than COMU in DMF. Furthermore, using various peptide synthetic models in solution and solid-phase synthesis, we reveal that they show better performance than HBTU in terms of preserving chiral integrity and coupling yields, but slightly worse performance than COMU.

Background: The carbonyl group at position 2 of N -acetylisatin behaves as an amide which is more susceptible to nucleophilic attack via ring-opening in the presence of nucleophiles. Because of this behavior, in the present work we describe the microwave synthesis of a series of α-ketoamide and bis -(α-ketoamide) derivatives via the facile ring-opening of N -acylisatin with different amines and diamines. The microwave irradiation afforded the product in less reaction time, higher yield and purity. Reaction of N -acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives with excellent yields and purities. Aminolysis of the ester derivatives with piperidine and morpholine afforded the same α-ketoamide derivatives obtained from direct aminolysis of N -acylisatin. The structures of the synthesized compounds were confirmed by FT-IR, NMR, X-ray and elemental analysis., Results: Reaction of N -acetylisatin and N -propoionylsatin with different amines and diamines afforded a series of α-ketoamide and bis -(α-ketoamide) derivatives respectively via the ring opening of N -acylisatins. The reaction was performed under conventional condition as well as microwave irradiation. The microwave irradiation afforded the product in less reaction time, higher yield and purity. Reaction of N -acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives in excellent yields and purities as observed from their spectral data. A plausible mechanism involves nucleophilic attack by methanol at C2 carbonyl carbon of N -acetylisatin and subsequent ring opening to generate the α-ketoester. Aminolysis of α-ketoester with amine afforded the same α-ketoamide which is obtained by direct aminolysis of N -acylisatin. The IR, NMR spectra, microanalyses, and single crystal X-ray diffraction confirmed the structures of the synthesized compounds., Conclusions: In conclusion, we have demonstrated that microwave irradiation could be employed efficiently for the synthesis of biologically important α-ketoamide and bis -(α-ketoamide) derivatives. The microwave irradiation has more advantageous over the classical method with regard to reaction time, solvent quantity, and product yield. Reaction of N -acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives with excellent yields and purities. Aminolysis of the methyl ester derivatives with amine under microwave irradiation afford the same α-ketoamide derivatives as obtained from direct aminolysis of N -acylisatins.

Background: Valproic acid (VPA) is a potent anticancer and antiangiogenic agent. However, design and synthesis of chemical derivatives with improved antiangiogenic and anticancer activities are still necessary. In this study a library of novel derivatives of VPA was synthesized and tested., Methods: A human liver cancer cell line (HepG2) and a human normal embryonic kidney cell line (HEK 293) were exposed to various concentrations of VPA derivatives for 24 hours and cell viability was checked by MTT colorimetric assay. Anti-angiogenic properties were evaluated in transgenic zebrafish embryos., Results: N-valproylglycine derivatives suppressed survival almost 70% (p value 0.001) in HepG2 cells but only 10-12% in HEK 293 cells (p value 0.133). They also suppressed angiogenic blood vessel formation by 80% when used between 2-20 μM in zebrafish embryos. Valproic acid hydrazides showed moderate level of anticancer activity by affecting 30-50% (p value 0.001) of cell viability in HepG2 cells and 8-10% in HEK293 cells (p value 0.034)., Conclusion: The majority of compounds in this study showed potent and stronger antiangiogenic and anticancer activity than VPA. They proved selectively toxic to cancer cells and safer for normal cells. Moreover, these compounds inhibited developmental angiogenesis in zebrafish embryos. Based on the fact that liver is a highly vascularized organ, in case of liver carcinoma these compounds have the potential to target the pathological angiogenesis and could be an effective strategy to treat hepatocellular carcinoma.

A series of novel cyano oximino sulfonate derivatives were prepared from the reaction of arylsulfonyl chloride with different cyanoacetamide-based oximes ranging from the simplest unsubstituted amide to analogues containing N-ethyl (mimicking the Oxyma template), N-piperidinyl and N-morpholinyl chains. In addition, the cyano oximes, N-hydroxybenzimidoyl cyanide and N-hydroxypicolinimidoyl cyanide were also used in the synthesis of the novel cyano oximino sulfonate derivatives. The structures of the prepared compounds were confirmed by (1)H-NMR, (13)C-NMR, and elemental analysis. The preliminary bioassays showed that some of the title compounds, such as 2-oxo-2-(piperidin-1-yl)-N-(tosyloxy)acetimidoyl cyanide (TsPipOx), N-(tosyloxy)benzimidoyl cyanide (TsPhOX), N-(naphthalen-2-ylsulfonyloxy)-2-oxo-2-(piperidin-1-yl)acetimidoyl cyanide (NpsPipOx), 2-amino-N-(naphthalen-2-ylsulfonyloxy)-2-oxoacetimidoyl cyanide (NpsAmOx), N-(naphthalen-2-ylsulfonyloxy)benzimidoyl cyanide (NpsPhCN), and N-(naphthalen-2-ylsulfonyloxy)picolinimidoyl cyanide (NpsPyCN), showed anti-proliferation effect on the mouse fibroblast L929. The calculated IC50-values were ranging between 36.5 µg/mL and 0.235 mg/mL. However the anti-proliferation effects seem to be cytostatic rather than cytotoxic. The compounds only minimize the growth activity without completely killing the cells.

Series of Schiff bases of valproic acid hydrazide, N-valproylglycine hydrazide and N-valproyl-4-aminobenzoyl hydrazide derivatives were synthesized and characterized by IR, NMR ((1)H- and (13)C-NMR) and elemental analysis. The prepared compounds were evaluated in transgenic zebrafish embryos (Tg: flil-1: enhanced green fluorescent protein (EGFP)) for antiangiogenic activity and in HepG2 liver carcinoma cell line for anti cancer activity. The Schiff bases of N-valproylglycine hydrazide derivatives were most potent in term of suppressing angiogenic blood vessels formation and anticancer activity at very low concentration, followed by the Schiff bases of valproic acid hydrazide derivatives which exhibited moderate activity, while the Schiff bases of N-valproyl-4-aminobenzoyl hydrazide derivatives, ethyl 4-(2-propylpentanamido)benzoate (VABE) and N-(4-(hydrazinecarbonyl)phenyl)-2-propylpentanamide (VABH) in contrast exhibited pro-angiogenic activity and weaker anticancer activity which mean that these derivatives targeted a common signaling pathway in term of affecting the blood vessels formation.

We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-protection and peptide coupling.

Background: Many efforts have been recently devoted to design, investigate and synthesize biocompatible, biodegradable polymers for applications in medicine for either the fabrication of biodegradable devices or as drug delivery systems. Many of them consist of condensation of polymers having incorporated peptide linkages susceptible to enzymatic cleavage. Polyamides (PAs) containing α-amino acid residues such as L-leucine, L-alanine and L-phenylalanine have been reported as biodegradable materials. Furthermore, polyamides (PAs) derived from C10 and C14 dicarboxylic acids and amide-diamines derived from 1,6-hexanediamine or 1,12-dodecanediamine and L-phenylalanine, L-valyl-L-phenylalanine or L-phenylalanyl-L-valine residues have been reported as biocompatible polymers. We have previously described the synthesis and thermal properties of a new type of polyamides-containing amino acids based on eight new symmetric meta-oriented protected diamines derived from coupling of amino acids namely; Fomc-glycine, Fmoc-alanine, Fomc-valine and Fomc-leucine with m-phenylene diamine or 2,6-diaminopyridine. Results revealed that incorporation of pyridine onto the polymeric backbone of all series decreases the thermal stability.Here we describe another family of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid linked to benzidine and 4,4'-oxydianiline to study the effect of the dicarboxylic acid as well as the amino acids on the nature and thermal stability of the polymers., Results: We report here the preparation of a new type of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid linked to benzidine and 4,4'-oxydianiline to study the effect of the dicarboxylic acid as well as the amino acids on the nature and thermal stability of polymers. The thermal properties of the polymers were evaluated by different techniques. Results revealed that structure-thermal property correlation based on changing the dicarboxylic acid monomer or the diamine monomer demonstrated an interesting connection between a single change (changing the dicarboxylic acids in each series while the diamine is fixed) and thermal properties. The newly prepared polymers may possess biodegradability and thus may find some applications as novel biomaterials., Conclusions: The thermal properties of the new type of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid (alanine and valine) linked to benzidine and 4,4'-oxydianiline were evaluated by thermal gravimetric (TG), differential thermal gravimetric (DTG) and differential thermal analysis (DTA) techniques. Results revealed that the structure-thermal property correlation based on changing the dicarboxylic acid monomer or the diamine monomer demonstrated an interesting connection between a single change (changing the dicarboxylic acids in each series while the diamine is fixed) and thermal properties. In addition, pyridine-containing polymers exhibited semicrystalline characteristic with melting temperature, Tm. where none of the valine-containing polymers showed a melting and crystallization peak indicating that the polymers were amorphous. This is expected since L-valine side chain can inhibit close packing and eliminate crystallization. The newly prepared polymers may possess biodegradability and thus may find some applications as novel biomaterials.

Peptide-bond formation is a pivotal process in the synthesis of peptide oligomers. Among the various coupling methodologies described, carbodiimides combine strong acylation potency and smooth reaction conditions, and they are commonly used in the presence of N-hydroxylamine additives. In recent years, acidic oxime templates, mainly ethyl 2-cyano-2-(hydroxyimino) acetate (Oxyma), have emerged as highly reactive alternatives to the classic and explosive-prone benzotriazolic additives, 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt). However, to achieve certain biochemical targets, less reactive species, such as N-hydroxysuccinimide (HOSu) esters, are often required to obtain stability under aqueous conditions. In the present study, we report on a new family of water-soluble N-alkyl-cyanoacetamido oximes, most of which have proven useful in the construction of active carbonates for the introduction of fluorenylmethoxycarbonyl (Fmoc) with minimal impact of dipeptide impurities. We performed a direct comparison of these new N-alkyl-cyanoacetamido oximes with HOSu in order to evaluate their capacity to retain optical purity and their coupling efficiency in the assembly of bulky residues.

A new family of sulfonate ester-type coupling reagents is described which differs in its leaving group. The sulfonate ester coupling reagents ethyl 2-cyano-2-(naphthalen-2-ylsulfonyloxyimino)acetate (NpsOXY), and ethyl 2-cyano-2-(tosyloxyimino)acetate (TsOXY) are more efficient alternatives to the benzotriazole sulfonate esters in terms of racemization suppression and coupling effectiveness. Both oxyma and its related sulfonate esters can be handled with a considerably lower risk than the explosive benzotriazole and its derivatives. 2-Oxopyridin-1(2H)-yl naphthalene-2-sulfonate (NpsOPy) and 2-oxopyridin-1(2H)-yl 4-methylbenzenesulfonate (TsOPy) sulfonate esters derived from 1-hydroxypyridin-2(1H)-one were also successfully used as new coupling reagents requiring a longer preactivation time during the coupling process. An improvement in yield and almost comparable optical purity to that of the 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) analogues was observed.

A series of new pyridazinylacetic acid derivatives were synthesized and have been investigated for their ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). All compounds were found to be more selective to the MAO-A isoform with compound 5d having the highest SI values. Computational study performed with a docking technique indicated the potential of these compounds in pyridazine-based MAO-A inhibitor drug development.

The coupling reaction of benzoic acid and nicotinic acid hydrazides with N- protected L-amino acids including valine, leucine, phenylalanine, glutamic acid and tyrosine is reported. The target compounds, N-Boc-amino acid-(N;-benzoyl)- and N- Boc-amino acid-(N;-nicotinoyl) hydrazides 5a-5e and 6a-6e were prepared in very high yields and purity using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl- methylene]-N-methyl-methanaminium hexafluorophosphate N-oxide (HATU) as coupling reagent. The antimicrobial activity of the Cu and Cd complexes of the designed compounds was tested. The products were deprotected affording the corresponding amino acid-(N;-benzoyl) hydrazide hydrochloride salts (7a-7e) and amino acid-(N;- nicotinoyl) hydrazide hydrochloride salts (8a-8e). These compounds and their Cu and Cd complexes were also tested for their antimicrobial activity. Several compounds showed comparable activity to that of ampicillin against S. aureus and E. coli.