Microwave-assisted synthesis of novel steroidal heterocyclic analogs as potent inhibitors of RANKL-induced osteoclastogenesis.

Osteoporosis is a significant public health issue in our aging population. It is an excessive bone resorption condition brought on by osteoclastogenesis, which makes bones more brittle. In the present work, a series of novel heterosteroidal derivatives have been synthesized using the microwave technique and were evaluated as antiosteoclastogenic agents. The structures of the newly synthesized compounds have been confirmed using analytical and spectral data. The antiosteoclastogenic activity of the newly synthesized compounds was estimated in vitro against osteoclast-differentiated cells from the RAW 264.7 cell line. The pregnenolone dimer 10, the pyridinotestosterone derivative 2, and the phenylnicotinonitrile pregnenolone derivative 8a attained the most promising antiosteoclastogenic activity displaying IC50 (the half maximal inhibitory concentration) values of 5.45 ± 5.30, 11.88 ± 2.09, and 13.40 ± 3.00 µM, respectively, in comparison with dimethyl itaconate (IC50 = 17.76 ± 3.20 µM) and alendronate (IC50 = 4.48 ± 1.89 µM) as reference compounds. Finally, an in silico ADME (Absorption, Distribution, Metabolism, and Excretion) study was conducted to evaluate the synthesized compounds' pharmacokinetic and drug-likeness properties. The results manifested that almost all the investigated compounds' properties were compatible with the specified optimal range, which indicates their reassuring pharmacokinetic properties.

Anti-cancer activity, and molecular docking of novel hybrid heterocyclic steroids revealed promising anti-hepatocellular carcinoma agent: Implication of cyclin dependent kinase-2 pathway.

To identify new steroidal agents with potential biological activities, we synthesized hybrid steroids containing thiazole, pyrazole, isoxazole, thiophene or phthalazine moiety. Epi-androsterone 1 reacted with phenylthiosemicarbazide to afford the corresponding androstane-4-phenyl-3-thiosemicarbazone derivative 2. The latter product was used in the synthesis of a series of annulated steroid derivatives. Also, Epi-androsterone 1 reacted with the thienopyridazine derivative 16 to afford the thieno[3,4-d]pyridazino-N-ylidenoandrostane derivative 17. Compound 17 reacted readily with electron-poor olefins to yield the corresponding phthalazine steroid derivatives. Detailed experimental and spectroscopic evidences for the structures of the newly synthesized compounds are explained. Compounds 3, 7, 8a, 12a, 14, 17 and 21a, were investigated individually as anticancer agents on different panel of human malignant cell lines. Moreover, a computer modelling investigation was performed to speculate the macromolecular targets for the most promising candidate. The results revealed a concentration-dependent reduction in the number of viable cells in all cancer cell lines. Most notably, compound 7 was the most effective compound against all tested cancer cell lines, especially against HepG2 cell line; therefore, the mode of action of this compound against HCC was investigated. Compound 7 was able to induce cell cycle arrest, and DNA fragmentation in HepG2 cells. Moreover, compound 7 induced apoptosis via upregulating the expression of caspase-3, -8, -9, P53, Bax and inhibiting the expression of BCL2, and CDK2 genes. Our results highlighted compound 7 as a promising anti-hepatocellular carcinoma agent, with theoretical, and practical potential binding affinity with CDK2; therefore, more investigations are required to elucidate its chemotherapeutic value as anti-HCC agent.

Synthesis and cytotoxic evaluation of novel hybrid estrane heterocycles as chemotherapeutic anti-cancer agents.

New synthesized hybrid steroidal heterocyclic compounds have received a lot of attention in view of their biological activities as anticancer agents. In this study, a novel class of hybrid estrane heterocyclic compounds were synthesized and evaluated by analytical and spectral data which proved the validity of these derivatives. The cytotoxicity of synthesized compounds 2a, 2b, 2c, 3b, 8, 10a, 10b, 13, 14, 16a and 19 against three human cell lines: breast cancer cells (MCF-7), prostate cancer cells (PC3), and liver cancer cells (HepG2) has been tested using MTT assay. Compounds 10a, 10b, 2c, and 14 revealed more inhibitory influence on MCF7, PC3 and HepG2 growth than the reference drug doxorubicin (Dox) after 24 h incubation. Noteworthy, the tested compounds 10a, 10b, 2c, and 14 exhibited the most pronounced effect in this respect. The results were confirmed by morphology study.

Synthesis of novel hybrid hetero-steroids: Molecular docking study augmented anti-proliferative properties against cancerous cells.

Hetero-steroids, hybrid anticancer agents, have received much interest in view of their numerous and promising biological activities. In this study, a novel class of hetero-steroids were synthesized, analytical and spectral data proved the validity of the novel synthesized steroid derivatives. The cytotoxicity of the synthesized compounds 2, 5, 6, 7, 10, 11, 12, 14, 15, 17 were evaluated using human hepatocellular carcinoma cell lines (HepG2 and Huh-7) and non-small cell lung cancer (A549) cell lines. The synthesized compounds reported a remarkable gradual decrease in the cell viability of the three tested cancer cell lines. It was observed that compounds 2 and 12 had the lowest IC50s and the highest cytotoxic effects against all tested cell lines. As attempt to explain the cytotoxic activity achieved by the tested compounds in the in vitro study, molecular simulation was done to reveal the activity of the tested compounds against four different proteins (CDK2, CYP19, JAK2, and BCL2) which are highly implicated in cancer regulation and progression. We found that compound 2, and 12 were the best docked compounds against all tested receptors, which was indicated by lowest binding energy compared to reference ligand. Interestingly enough, our molecular study was in agreement with the cytotoxic activity. As future prospective, we are recommending further study on compounds 2, and 12 against the four different proteins to prove their mode of action.

Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study.

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa -fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.

Synthesis and Evaluation of Novel Cholestanoheterocyclic Steroids as Anticancer Agents.

Modification of steroid molecules by introducing heterocyclic ring into the core structure of steroids has been utilized as an attractive approach for either cancer prognosis or diagnosis. Several new cholestanoheterocyclic steroids were synthesized, and analytical and spectral data proved the validity of the novel synthesized steroid derivatives. The cytotoxicity of synthesized compounds 3, 4, 5, 7, 9, 10, 13, 15b, and 16b was evaluated using human colorectal cancer HCT 116 and Caco-2, cervical cancer HeLa, hepatoma HepG2, and breast cancer MCF7 cell lines. Intriguingly, compound 13 has the highest cytotoxic effect when applied on the majority of cancer cells. In conclusion, compound 13 may be considered as a promising anticancer candidate against all cancer cell lines, because it recorded the lowest IC50 of the majority of the cancer cell lines used. Furthermore, a molecular docking study was employed to determine the binding modes against aromatase cytochrome P450 (CYP19), cyclin-dependent kinase 2 (CDK2), and B-cell lymphoma (BCL-2) proteins, which are major proteins involved in the pathogenesis of cancer. Molecular docking analyses revealed that compounds 13, 3, and 5 (free energy of binding = - 9.2, - 9.1, and - 9.0 kcal/mol, respectively) were the best docked ligand against aromatase CYP19; compounds 16b, 3, 9, and 10 (free energy of binding = - 9.6, - 9.3, and - 9.2 kcal/mol, respectively) were the best docked ligand against CDK2, while compounds 15b, 16b, and 13 (free energy of binding = - 9.1, - 9.0, and- 8.7 kcal/mol, respectively) were the best docked ligand against BCL2. In conclusion, compounds 3, 13, and 16b were the most promising compounds with the lowest IC50s against most of the tested cancer cell lines, and they displayed the lowest binding energies, critical hydrogen bonds, and hydrophobic interactions with the three molecular targets compared to other tested compounds.

The Effect of Newly Synthesized Heterosteroids on miRNA34a, 98, and 214 Expression Levels in MCF-7 Breast Cancer Cells.

Hybrid anticancer drugs have emerged as great therapeutic options that can effectively overcome most obstacles facing conventional anticancer drugs. miRNAs are considered as class of non-coding RNAs that can negatively regulate protein coding gene expression. miRNA expression is commonly altered in cancer cells. The current work aimed to test the effect of new pro-apoptotic heterosteroids on some drug resistance related miRNAs expression levels (miRNA34a, 98, and 214) in MCF-7 breast cancer cells. After cell treatment with these compounds 4, 6, 7, 13, 18, 21, 22 and 24, miRNAs were extracted and subjected to reverse transcription and subsequent PCR amplification using Real Time-PCR technique. The expression levels of miR-34a, miR-98 and miR-214 were quantitatively determined. The study revealed that the expression levels of miR-34a, miR-98 and miR-214 were up-regulated upon treatment with tamoxifen, which was used as a positive control drug, as compared to control cells,. Strikingly, the levels of miR-34a, miR-98 and miR-214 expression were significantly down-regulated when treated with most of the new heterosteroids as compared to control cells. These results could indicate the promising effects of these new heterosteroids on reducing drug resistance as compared to tamoxifen drug. As well established, cells develop drug resistance to tamoxifen.

Novel pregnenolone derivatives modulate apoptosis via Bcl-2 family genes in hepatocellular carcinoma in vitro.

A series of pregnenolone derivatives were synthesized and assessed for anti-cancer activity against hepatocellular carcinoma cell line (HepG2). The synthesized hetero-steroids (compounds 3, 4, 5, 6, 7, 8a and 8b) were evaluated for their cytotoxic activities using MTT (3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assay. Apoptotic activity was assessed using dual acridine orange/ethidium bromide staining method and DNA fragmentation assay. Pro-apoptotic genes (Bax and Bak) and anti-apoptotic genes (Bcl-2 and Bcl-xL) were analyzed using quantitative real time PCR. The results revealed that compounds 4 and 6 displayed cytotoxic activity (IC50s, 36.97 ±â€¯2.18 and 18.46 ±â€¯0.64 µM, respectively), while compounds 5 and 7 exhibited weak cytotoxic activity (IC50s, 93.87 ±â€¯8.30 µM and 93.48 ±â€¯4.14 µM, respectively). All synthesized heterocyclic pregnenolone derivatives induced apoptosis through DNA fragmentation. Compounds 4 and 6 increased early and late apoptotic cell percentages while compounds 3, 5, 7 and 8b increased either early or late apoptotic cell percentage. Moreover, compounds 3, 6 and 8b up-regulated the expression level of Bak gene. On the other hand, compounds 4, 5, 7 and 8a down-regulated the Bcl-2 expression level, besides, compounds 5, 7 and 8a down-regulated the Bcl-xL expression level. Compounds 5, 7, 8a and 8b increased the Bak/Bcl-xL ratio, besides, compound 8a raised the Bax/Bcl-xL ratio whereas compound 5 elevated Bax/Bcl-2 and Bak/Bcl-2 ratios. The present work introduced novel pro-apoptotic pregnenolone derivatives that acted against HepG2 cells through DNA fragmentation, apoptotic morphological changes and were able to increase the pro-apoptotic/anti-apoptotic ratios of Bcl-2 family genes. This study particularly revealed that the cytotoxic compound 4 is the most promising pro-apoptotic compound among other synthesized derivatives where it induced apoptosis (late and early) through the down-regulation of Bcl-2 gene expression level.

Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs.

Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically important properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and many structure-activity relationships have been confirmed by such synthetic modifications. Several studies demonstrate that steroidal heterocyclic derivatives can be effective in the prevention and treatment of many types of hormone-dependent cancers. The present review is a concise report on steroidal heterocyclic derivatives, with special emphasis on steroid heterocyclic derivatives with 5 membered rings or six-membered rings having interesting therapeutic potential as enzyme inhibitors and cytotoxic drugs to be used as candidates for anti-cancer drug development.

Synthesis, Characterization, and Evaluation of Cytotoxic Effects of Novel Hybrid Steroidal Heterocycles as PEG Based Nanoparticles

Anticancer agents featuring hybrid molecules can improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized heterocyclic steroids of promising anticancer effects loaded in polyethylene glycol (PEG)•based nanoparticles form. Several heterocyclic steroids (1-9) were synthesized via multicomponent reactions (MCRs) and confirmed via the analytical and spectral data. Compounds 1, 2, 3, 4, 5, 6, 7 and 9, were investigated individually in their free and PEG based nano-size hybrid forms as anticancer agents against three human cell lines: hepatocellular carcinoma cells (HepG2); breast cancer cells (MCF-7); and colon cancer cells (HCT116). The neutral red supravital dye uptake assay was employed. Compound 6 in its PEG based nano-size form exhibited the best cytotoxic effects against HepG2 and HCT116 cell lines, with IC50 values of 2.44 µmol/l and 2.59 µmol/l, respectively. In addition, it demonstrated a low IC50 value against MCF-7 (3.46µmol/l) cells. This study introduced promising anticancer agents acting through conversion into PEG-based nanoparticles.

Evaluation of heterocyclic steroids and curcumin derivatives as anti-breast cancer agents: Studying the effect on apoptosis in MCF-7 breast cancer cells.

Anticancer agents consisting of hybrid molecules are used to improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized hetero-steroids of promising anticancer effects. Besides, the pro-apoptotic effects of new compounds were investigated extensively. Several pyrimidino-, triazolopyrimidino-, pyridazino-, and curcumin-steroid derivatives were synthesized, elucidated and confirmed using the spectral and analytical data. The synthesized hetero-steroids, compounds 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 22 and 24, were tested for their cytotoxic effects versus human breast cancer cells (MCF-7) using neutral red supravital dye uptake assay. Compound 24 (IC50=18µM) showed more inhibitory influence on MCF-7 growth. Using QRT-PCR (Quantitative real time-polymerase chain reaction), CCND1, Survivin, BCL-2, CDC2, P21 and P53, genes expression levels were investigated. The study results disclose that compounds 4, 7, 18, 24 knocked down the expression levels of CCND1, Survivin, BCL-2 and CDC2. However, P21 and P53 were up-regulated by compounds 21, 22. This study introduced promising pro-apoptotic anticancer agents acting through the modulation of key regulators of apoptosis and cell cycle genes.

Synthesis of novel steroidal curcumin derivatives as anti-Alzheimer's disease candidates: Evidences-based on in vivo study.

Alzheimer's disease (AD) is a complex disease in which a single monofunctional 'targeted' drug is uneffective for management. Hybrid drugs that impact multiple targets simultaneously are better at controlling such complex disease systems. Hybrid agents were synthesized through the combination of the steroid moiety with curcumin molecule. Also novel curcumin analogues containing promising heterocyclic nucleus fused to the essential pharmacophoric feature of the curcumin moiety, were synthesized. The aim of the present study was extended to elucidate the efficacy of these novel synthesized compounds in the regression of AD induced in adult female albino rats. The results revealed that treatment of AD groups with compounds 3, 5, 8c or rivastigmin experienced significant increase in brain Ach, GSH, paraoxenase and BCL2 levels with respect to untreated group associated with significant decrease in brain AchE activity, urinary 8-OHG level, serum Caspase-3 level and brain P53 level relative to the untreated group. Immunohistochemical investigation revealed that the selected treatments caused marked increase in ChAT positive cells. These findings were documented by the histological investigation of the brain tissue. The activity of tested compounds showed gradual increase from compound b followed by compound 8c then compound 5. The anti-cholinesterase potential, anti-oxidant properties and anti-apoptotic activity are responsible for the anti-Alzheimer's disease potential of these compounds.

Heterocyclizations of pregnenolone: novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3-b]pyridine derivatives and their cytotoxicity evaluations.

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with 4-phenyl-3-thiosemicarbazide gave the thiosemicarbazone derivative 3. The latter compound underwent heterocyclization reactions to give the thiazolyl hydrazonoandrostane and pyrazolyl semicarbazidoandrostane derivatives 5a-d, and 9a-d, respectively. On the other hand compound 1 reacted with either malononitrile or ethyl cyanoacetate to give the Knoevenagel condensated products 11a and 11b, respectively. Compounds 11a,b afforded the thiophenyl pregnane derivatives 12a and 12b, respectively, their reactivity toward some chemical reagents was studied. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference drug, doxorubicin.

One-pot three-component synthesis of novel heterocyclic steroids as a central antioxidant and anti-inflammatory agents.

Oxidative stress and inflammation have been implicated in several neurodegenerative and developmental brain disorders. The present work was devoted to the design and synthesis of novel steroid derivatives bearing promising heterocyclic moiety that would act to reduce neuro-inflammation and oxidative stress in brain. The novel heterocyclic steroids were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The tested compounds were assayed in the model of neuro-inflammation produced in rats by cerebral lipopolysaccharide injection. The intracerebral administration of bacterial endotoxin resulted in cerebral inflammatory state evidenced by increased malondialdehyde (MDA), decreased reduced glutathione (GSH) level, increased nitric oxide as well as increased acetylcholinesterase (AChE) activity in the brain. Compounds 6, 10, 8b and 13a markedly increased reduced glutathione. Malondialadehyde and nitric oxide levels were reduced to normal values after treatment with all tested compounds. AChE activity was normalized by compound 8b and reduced to below normal values by compounds 10 and 14a. These results are exciting in that these agents might be useful candidates in treatment of cerebral inflammation.

Sterol C24-methyltransferase: Physio- and stereo-chemical features of the sterol C3 group required for catalytic competence.

Sterol C24-methyltransferases (24-SMTs) catalyze the electrophilic alkylation of Δ(24)-sterols to a variety of sterol side chain constructions, and the C3- moiety is the primary determinant for substrate binding by these enzymes. To determine what specific structural features of the C3-polar group ensure sterol catalysis, a series of structurally related C3-analogs of lanosterol that differed in stereochemistry, bulk and electronic properties were examined against the fungal 24-SMT from Paracoccidioides brasiliensis (Pb) which recognize lanosterol as the natural substrate. Analysis of the magnitude of sterol C24-methylation activity (based on the kinetic constants of V(max)/K(m) and product distributions determined by GC-MS) resulting from changes at the C3-position in which the 3ß-OH was replaced by 3α-OH, 3ß-acetyl, 3-oxo, 3-OMe, 3ß-F, 3ß-NH(2) (protonated species) or 3H group revealed that lanosterol and five substrate analogs were catalyzed and yielded identical side chain products whereas neither the 3H- or 3α-OH lanosterol derivatives were productively bound. Taken together, our results demonstrate a chemical complementarity involving hydrogen bonding formation of specific active site contacts to the nucleophilic C3-group of sterol is required for proper orientation of the substrate C-methyl intermediate in the activated complex.

Cytotoxicity and gene expression profiles of novel synthesized steroid derivatives as chemotherapeutic anti-breast cancer agents.

Anti-cancer agents which combine two biologically active compounds in one such as steroidal heterocyclic derivatives attain both hormone and cytotoxic effects on cancer cells. The aim of the present study is to synthesize and evaluate new potential chemotherapeutic anti-breast cancer agents. Several pyridazino-, pyrimido-, quinazolo-, oxirano- and thiazolo-steroid derivatives were synthesized. The structure of the novel steroid derivatives was confirmed using the analytical and spectral data. The most structurally promising of the novel synthesized steroid derivatives, compounds 8, 12, 17, 20, 22c, 24c, 30a and 30b, were investigated individually as anti-breast cancer agents against human breast cancer cells (MCF-7) using sulforhodamine B (SRB) assay. The tested compounds 17, 20, 22c and 8 showed potent broad spectrum cytotoxic activity in vitro after 48 h incubation. Compound 17 (IC(50)=2.5 µM) exhibited more inhibitory influence on MCF-7 growth than the reference drug doxorubicin (Dox) (IC(50)=4.5 µM) after 48 h incubation. Also, the present study showed that all the tested steroid derivatives exhibited significant depletion with various intensities in gene expression of breast cancer related genes (VEGF, CYP19 and hAP-2γ). Noteworthy, compounds 17, 20 and 22c showed the most pronounced effect in this respect.

Evaluation of anti-inflammatory, anti-nociceptive, and anti-ulcerogenic activities of novel synthesized thiazolyl and pyrrolyl steroids.

Developing new therapeutic agents that can overcome gastrointestinal injury and at the same time could lead to an enhanced anti-inflammatory effect becomes an urgent need for inflammation patients. Thiazolyl and pyrrolyl steroids were synthesized via straight forward and efficient methods and their structures were established based on their correct elemental analysis and compatible IR, (1) H-NMR, (13) C-NMR, and mass spectral data. The dihydrothiazolyl-hydrazonoprogesterone 12 and the aminopyrrolylprogesterone 16a showed anti-inflammatory, antinociceptive, and anti-ulcerogenic activity with various intensities. Edema were significantly reduced by both doses of tested compounds (25 and 50 mg/kg) at 2, 3, and 4 h post-carrageenan. The high dose of compound 16a was the most effective in alleviating thermal pain. Gastric mucosal lesions, caused in the rats by the administration of ethanol or indomethacin (IND), were significantly inhibited by each of the two tested compounds. These results provide a unique opportunity to develop new anti-inflammatory drugs which devoid the ulcerogenic liabilities associated with currently marketed drugs.

Synthesis of modified steroids as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agents.

The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study.

Development of new indole-derived neuroprotective agents.

There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. The present study aimed at synthesizing new functionalized indole derivatives with structures justifying neuroprotective activity using L-tryptophan (TRP) as starting material. The potential neuroprotective effect of these newly synthesized agents against acrylamide (ACR) induced neurotoxicity was investigated in adult female rats. The novel indole derivatives, indolylmethyl pyridine derivatives 9a,b, pyrimidinylindolyl propanone derivatives 12a-c, pyrazolylindolyl propanone derivatives 14a,b, and indolyl tetrazolopropanoic acid derivative 17 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [ip, 50mgkg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with the indole derivatives 9b, 12c, 14a, and 17 (ip, 50mgkg(-1) b. wt.) prior to ACR produced neuroprotective activity with various intensities depending on the structure of each compound. Compound 17 in which the tetrazole ring was attached to the TRP moiety ranked as the strongest neuroprotective agent. All the tested compounds have been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by ACR administration.

Potent neuroprotective role of novel melatonin derivatives for management of central neuropathy induced by acrylamide in rats.

Acrylamide (ACR) has been shown to be a neurotoxic agent for both laboratory animals and human. The present study aimed at synthesizing new functionalized melatonin derivatives bearing promising heterocyclic moiety that could be expected to have protective effect against ACR-induced neurotoxicity in adult female rats. The novel melatonin derivatives 4, 6, 7 and 11 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [i.p., 50 mg kg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with melatonin derivatives 4, 6, 7 and 11 (i.p., 50 mg kg(-1) b. wt) prior to ACR produced significant decrease in brain MDA level and LDH activity with concomitant significant increase in brain monoamines and antioxidant enzymes activity. It could be concluded that the new synthesized melatonin derivatives exhibited promising protective activity against ACR-induced neurotoxicity.