Design, in silico study, synthesis and evaluation of hybrid pyrazole substituted 1,3,5-triazine derivatives for antimalarial activity.

OBJECTIVES: Malaria is a significant global health challenge, particularly in Africa, Asia, and Latin America, necessitating immediate investigation into innovative and efficacious treatments. This work involves the development of pyrazole substituted 1,3,5-triazine derivatives as antimalarial agent. METHODS: In this study, ten compounds 7(a-j) were synthesized by using nucleophilic substitution reaction, screened for in silico study and their antimalarial activity were evaluated against 3D7 (chloroquine-sensitive) strain of P. falciparum. KEY FINDING: The present work involves the development of hybrid trimethoxy pyrazole 1,3,5-triazine derivatives 7 (a-j). Through in silico analysis, four compounds were identified with favorable binding energy and dock scores. The primary focus of the docking investigations was on the examination of hydrogen bonding and the associated interactions with certain amino acid residues, including Arg A122, Ser A108, Ser A111, Ile A164, Asp A54, and Cys A15. The IC50 values of the four compounds were measured in vitro to assess their antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum. The IC50 values varied from 25.02 to 54.82 µg/mL. CONCLUSION: Among the ten derivatives, compound 7J has considerable potential as an antimalarial agent, making it a viable contender for further refinement in the realm of pharmaceutical exploration, with the aim of mitigating the global malaria load.

Hybrid PABA-glutamic acid conjugated 1,3,5-triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme.

Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first-line treatments. Also because of the disruption in malaria prevention services during the COVID-19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5-triazine hybrids conjugated with PABA-glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine-sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non-cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2.

Ebselen is a selenoorganic chiral compound with antioxidant properties comparable to glutathione peroxidase. It is also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one. In studies examining its numerous pharmacological activities, including antioxidant, anticancer, antiviral, and anti-Alzheimer's, ebselen has demonstrated promising results. This review's primary objective was to emphasize the numerous synthesis pathways of ebselen and their efficacy in fighting cancer. The data were collected from multiple sources, including Scopus, PubMed, Google Scholar, Web of Science, and Publons. The starting reagents for the synthesis of ebselen are 2-aminobenzoic acid and N-phenyl benzamide. It was discovered that ebselen has the ability to initiate apoptosis in malignant cells and prevent the formation of new cancer cells by scavenging free radicals. In addition, ebselen increases tumor cell susceptibility to apoptosis by inhibiting TNF-α mediated NF-jB activation. Ebselen can inhibit both doxorubicin and daunorubicin-induced cardiotoxicity. Allopurinol and ebselen administered orally can be used to suppress renal ototoxicity and nephrotoxicity. Due to excessive administration, diclofenac can induce malignancy of the gastrointestinal tract, which ebselen can effectively suppress. Recent research has demonstrated ebselen to inhibit viral function by binding to cysteine-containing catalytic domains of various viral proteases. It was discovered that ebselen could inhibit the catalytic dyad function of Mpro by forming an irreversible covalent bond between Se and Cys145, thereby altering protease function and inhibiting SARS-CoV-2. Ebselen may also inhibit the activation of endosomal NADPH oxidase of vascular endothelial cells, which is believed to be required for thrombotic complications in COVID-19. In this review, we have included various studies conducted on the anticancer effect of ebselen as well as its inhibition of SARS-CoV-2.

In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors.

OBJECTIVES: Drug resistance in malaria parasites necessitates the development of new antimalarial drugs with unique mechanisms of action. In the present research work, the PABA conjugated 1,3,5-triazine derivatives were designed as an antimalarial agent. METHODS: In this present work, a library of two hundred-seven compounds was prepared in twelve different series such as [4A (1-23), 4B(1-22), 4C(1-21), 4D(1-20), 4E(1-19), 4F(1-18), 4G(1-17), 4H(1-16), 4I(1-15), 4J(1-13), 4K(1-12) and 4L(1-11) ] respectively using different primary and secondary aliphatic and aromatic amines. Ten compounds were ultimately selected through in silico screening. They were synthesized by conventional and microwave-assisted methods followed by in vitro antimalarial evaluations performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum. RESULTS: The docking results showed that compound 4C(11) had good binding interaction with Phe116, Met55 (-464.70 kcal/mol) and Phe116, Ser111 (-432.60 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. Furthermore, in vitro, antimalarial activity results indicated that compound 4C(11) showed potent antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain of P. falciparum along with IC50 (14.90 µg mL-1) and (8.30 µg mL-1). CONCLUSION: These PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.

Molecular docking and antimalarial evaluation of hybrid para-aminobenzoic acid 1,3,5 triazine derivatives via inhibition of Pf-DHFR.

In this study, a structurally guided pharmacophore hybridization strategy is used to combine the two key structural scaffolds, para-aminobenzoic acid (PABA), and 1,3,5 triazine in search of new series of antimalarial agents. A combinatorial library of 100 compounds was prepared in five different series as [4A (1-22), 4B (1-21), 4 C (1-20), 4D (1-19) and 4E (1-18)] using different primary and secondary amines, from where 10 compounds were finally screened out through molecular property filter analysis and molecular docking study as promising PABA substituted 1,3,5-triazine scaffold as an antimalarial agent. The docking results showed that compounds 4A12 and 4A20 exhibited good binding interaction with Phe58, IIe164, Ser111, Arg122, Asp54 (-424.19 to -360.34 kcal/mol) and Arg122, Phe116, Ser111, Phe58 (-506.29 to -431.75 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. These compounds were synthesized by conventional as well as microwave-assisted synthesis and characterized by different spectroscopic methods. In-vitro antimalarial activity results indicated that two compounds 4A12 and 4A20 showed promising antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum with IC50 (1.24-4.77 µg mL-1) and (2.11-3.60 µg mL-1). These hybrid PABA substituted 1,3,5-triazine derivatives might be used in the lead discovery towards a new class of Pf-DHFR inhibitors.Communicated by Ramaswamy H. Sarma.

A Review Of Preclinical Tools To Validate Anti-Diarrheal Agents.

BACKGROUND: Since their inception, preclinical experimental models have played an important role in investigating and characterizing disease pathogenesis. These in vivo, ex vivo, and in vitro preclinical tests also aid in identifying targets, evaluating potential therapeutic drugs, and validating treatment protocols. INTRODUCTION: Diarrhea is a leading cause of mortality and morbidity, particularly among children in developing countries, and it represents a huge health-care challenge on a global scale. Due to its chronic manifestations, alternative anti-diarrheal medications must be tested and developed because of the undesirable side effects of currently existing anti-diarrheal drugs. METHODS: Several online databases, including Science Direct, PubMed, Web of Science, Google Scholar and Scopus, were used in the literature search. The datasets were searched for entries of studies up to May, 2022. RESULTS: The exhaustive literature study provides a large number of in vivo, in vitro and ex vivo models, which have been used for evaluating the mechanism of the anti-diarrheal effect of drugs in chemically-, pathogen-, disease-induced animal models of diarrhea. The advances and challenges of each model were also addressed in this review. CONCLUSION: This review encompasses diverse strategies for screening drugs with anti-diarrheal effects and covers a wide range of pathophysiological and molecular mechanisms linked to diarrhea, with a particular emphasis on the challenges of evaluating and predictively validating these experimental models in preclinical studies. This could also help researchers find a new medicine to treat diabetes more effectively and with fewer adverse effects.

Molecular docking and antimalarial evaluation of novel N-(4-aminobenzoyl)-l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitors.

Malaria has been a source of concern for humans for millennia; therefore in the present study we have utilized in-silico approach to generate diverse anti-malarial hit. Towards this, Molinspiration cheminformatics and Biovia Discovery Studio (DS) 2020 were used to conduct molecular modelling studies on 120 designed compounds. Furthermore, the TOPKAT module was used to evaluate the toxicity of the screened compounds. The CDOCKER docking technology was used to investigate protein-ligand docking against the Pf-DHFR-TS protein (PDB ID: 1J3I and 1J3K). These compounds were synthesized using a conventional and microwave-assisted nucleophilic substitution reaction, and they were characterized using a variety of physicochemical and spectroscopic methods. Among the ten compounds tested, Df3 had the highest antimalarial activity against the chloroquine-resistant (Dd2) strain, with an IC50 value of 9.54 µg mL-1 and further demonstrate, molecular dynamics (MD) simulation studies and estimation of MM-PBSA-based free binding energies of docked complexes with 1J3I and 1J3K were carried out. The discovery of a novel class of Pf-DHFR inhibitors can be accomplished using this hybrid scaffold. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03400-2.

Microwave synthesis and antimalarial screening of novel 4-amino benzoic acid (PABA)-substituted pyrimidine derivatives as Plasmodium falciparum dihydrofolate reductase inhibitors.

Antimalarial drug resistance is a major threat due to the emerging resistance to all the available drugs in the market. In an approach to develop alternative drugs, a novel class of Pf-DHFR inhibitors was developed using pyrimidine as the core nucleus and substituting the 4- and 6- positions with amines and 4-amino benzoic acid (PABA) to avoid the problem of drug resistance. The resultant compounds 3(a-j) after primary in silico screening and filtering were synthesized using microwave efficiently in high yield and reduced time period compared to conventional synthesis. The antimalarial assay was performed in vitro, against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum using chloroquine as a reference standard. The IC50 values were in the range of 5.26-106.76 µg/ml for 3D7 and in Dd2 the value ranges from 4.71 to 112.98 µg/ml. Compounds 3d, 3e, 3f and 3h showed significant antimalarial activity against both the strains of P. falciparum with no cytotoxicity against fibroblast cell line and 3f was found to be the most potent among them. The hemolysis assay of all the compounds in fresh erythrocytes showed insignificant hemolysis below 5% at a higher dose level. Hence, the present study suggests the possible utility of PABA-substituted pyrimidine scaffold for further development of new Pf-DHFR inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03236-w.

Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors.

Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition.

Acute and sub-chronic toxicity studies of Benincasa hispida (Thunb.) cogniaux fruit extract in rodents.

The objective of the present study was to evaluate the safety of standardized 70% ethanolic extract of Benincasa hispida fruit pulp (HABH) in rodents. Chemical characterization of HABH has been done by GC-MS and dimethylsulfoxonium formyl methylide, l-(+)-ascorbic acid and 2,6-dihexadecanoate were identified as major compounds in the extract. Acute oral toxicity study of HABH was done according to the Organization for Economic Cooperation and Development (OECD) guideline, by 'up and down' method, using the limit test at 2000 mg/kg, body weight in mice and were observed up to 14 days. In sub-chronic oral toxicity study, HABH was administered to Wistar rats at doses of 1000, 200 and 40 mg/kg b. w. per day for 90 days. In acute toxicity study, there was no mortality and no behavioural signs of toxicity at the limit test dose level (2000 mg/kg b. w.). In sub-chronic oral toxicity study, there was no significant difference observed in the consumption of food and water, body weight and relative organ weights. Haematological, serum biochemical and urine analysis revealed the non-adverse effects of prolonged oral consumption of HABH. The histopathologic examination did not show any differences in vital organs. Based on our findings, HABH, at dosage levels up to 1000 mg/kg b. w., is non-toxic and safe for long term oral consumption.

Discovery of potential 1,3,5-Triazine compounds against strains of Plasmodium falciparum using supervised machine learning models.

The Malaria burden was an escalating global encumbrance and need to be addressed with critical care. Anti-malarial drug discovery was integrated with supervised machine learning (ML) models to identify potent thiazolyl-traizine derivatives. This assimilated approach of Direct Kernel-based Partial Least Squares regression (DKPLS) with molprint 2D fingerprints in Quantitative Structure Activity Relationship models was utilized to map the knowledge of known actives and to design novel molecules. This QSAR study had revealed the structural features required for better antimalarial activity. Two of the molecules which were designed based on the results of this QSAR study, had shown good percentage of parasitemia against both chloroquine sensitive (3D7) and chloroquine resistant (Dd2) strains of Plasmodium falciparum respectively. The IC50 of 201D and 204D was 3.02 and 2.17 µM against chloroquine resistant Dd2 strain of Plasmodium falciparum. This result had proved the efficiency of a multidisciplinary approach of medicinal chemistry and machine learning for the design of novel potent anti-malarial compounds.

A Comprehensive Review on Preclinical Diabetic Models.

BACKGROUND: Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. INTRODUCTION: Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. METHODS: The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. RESULTS: A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. CONCLUSION: This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.

In silico ADMET study, docking, synthesis and antimalarial evaluation of thiazole-1,3,5-triazine derivatives as Pf-DHFR inhibitor.

BACKGROUND: Plasmodium falciparum dihydrofolate reductase (Pf-DHFR) is an essential enzyme in the folate pathway and is an important target for antimalarial drug discovery. In this study a modern approach has been undertaken to identify new hits of thiazole-1,3,5-triazine derivatives as antimalarials targeting Pf-DHFR. METHODS: The library of 378 thiazole-1,3,5-triazines were designed and subjected to ADME analysis. The compounds having optimal ADME score, was then evaluated by docking against wild and mutant Pf-DHFR complex. The resultant compound after screening from above these two methods were synthesized, and assayed for in vitro antimalarial against chloroquine-sensitive (3D-7) and chloroquine resistant (Dd-2) strains of P. falciparum. RESULTS: Twenty compounds were identified from the dataset based on considerable AlogP98 vs. PSA_2D confidence ellipse, ADME filter and TOPKAT toxicity analysis. Majority of compounds showed interaction with Asp54, Arg59, Arg122 and Ile 164 in docking analysis. Entire set of tested derivatives exhibited considerable activity at the tested dose against sensitive strain with IC50 values varying from 10.03 to 54.58 µg/ml. Furthermore, against chloroquine resistant strain, eight compounds showed IC50 from 11.29 to 40.92 µg/ml. Compound A5 and H16 were found to be the most potent against both the strains of P. Falciparum. CONCLUSION: Results of the study suggested the possible utility of thiazole-1,3,5-triazines as new lead for identifying new class of Pf-DHFR inhibitor.

Review on Synthetic Chemistry and Antibacterial Importance of Thiazole Derivatives.

BACKGROUND: Thiazole is one of the leading heterocyclic five-member ring compounds that contain nitrogen and sulphur atom. Many natural and/or synthetic compounds contain thiazole as an essential moiety and possess diverse therapeutic activities. The thiazole ring was modified at different positions to generate new molecules with potent antibacterial activities. Thus, the present review enumerates the antibacterial importance of thiazole and its derivatives. METHOD: The mining of literature has been performed using different database which includes only peer-reviewed journals. The quality of retrieved papers was appraised using standard tools. Moreover, the significant papers were described in detail to focus on thiazole derivatives showing considerable antibacterial activity. RESULT: The present review describes the chemistry, SAR (Structure Activity Relationship) studies and antibacterial importance of thiazole with different synthetic procedures. CONCLUSION: This particular study certainly benefits the researchers interested in exploiting the antibacterial activity of thiazoles in search of novel agents.

Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent.

BACKGROUND: The thiazolide nitazoxanide (NTZ) is a broad-spectrum antiinfective drug that adversely affects viability, growth, and proliferation of a range of extracellular and intracellular protozoan, helminths, anaerobic and microaerophilic bacteria, and viruses. METHOD: Current review compiled the potential chemotherapeutic efficacy of NTZ against a variety of such disease-causing macro and/or micro-organisms as well as neoplastic cells, using various search engines viz. Web of Science, Scopus and Pub- Med up to February 2017. RESULT: The most accepted anti-infective mechanism of NTZ involves impairment of the energy metabolism in anaerobic pathogens by inhibition of the pyruvate: ferredoxin/ flavodoxin oxidoreductase (PFOR). In parasitic-protozoan NTZ also induces lesions/voids in the cell membrane and depolarises the mitochondrial membrane along with the inhibition of quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase. NTZ also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates a gene (avr-14 gene) encoding for the alphatype subunit of glutamate-gated chloride ion channel present in the nematodes. Apart from well recognized non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also showed a variety of other antibacterial mechanisms viz. inhibits pyruvate dehydrogenase in the Escherichia coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria and stimulates host macrophage autophagy in the tubercular patients. NTZ also suppresses the viral replication by inhibiting maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Additionally, NTZ expresses inhibitory effect on the tumour cell progression by modulating drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activities and c-Myc inhibition. CONCLUSION: These potentially versatile molecular interactions of NTZ within invading pathogen(s) and immunomodulatory efficacy over the hosts, justify the multifunctional chemotherapeutic significance of this chemical agent.

Design, synthesis and antimalarial screening of some hybrid 4-aminoquinoline-triazine derivatives against pf-DHFR-TS.

Existing antifolate antimalarial drugs have shown resistance due to the mutations at some amino acid positions of Plasmodium falciparum DHFR-TS. In the present study, to overcome this resistance, a new series of hybrid 4-aminoquinoline-triazine derivatives were designed and docked into the active site of Pf-DHFR-TS (PDB i.d. 1J3K) using validated CDOCKER protocol. Binding energy was calculated by applying CHARMm forcefield. Binding energy and the pattern of interaction of the docked compounds were analysed. Fifteen compounds were selected for synthesis based on their binding energy values and docking poses. Synthesized compounds were characterised by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy and were screened for antimalarial activity against 3D7 strain of Plasmodium falciparum.

Synthesis, Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4-aminoquinoline-1,3,5-triazine Derivatives Against Wild and Mutant Malaria Parasites.

A new series of hybrid 4-aminoquinoline-1,3,5-triazine derivatives was synthesized by a four-step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine-sensitive (3D-7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P. falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) type pf-DHFR-TS to highlight the structural features of hybrid molecules.

Synthesis, SAR and antibacterial activity of hybrid chloro, dichloro-phenylthiazolyl-s-triazines.

A series of hybrid novel chloro (1a-9a) and dichloro (10b-18b) phenylthiazolyl-s-triazine were synthesized and subsequently subjected to their antibacterial activity against three gram positive viz. Lactobacillus casei (NCIM-2651); Bacillus cereus (NCIM-2458); Staphylococcus aureus (NCIM-2120) and three gram negative viz Salmonella typhimurium (NCIM-2501); Escherichia coli (NCIM-2065); Klebsiella aerogenes (NCIM-2098). The SAR studies around the lead compound revealed that introduction of electron withdrawing groups and amino (-NH-) and mercapto (-S-) linker bridge seemed more promising towards antibacterial activity. Moreover, the virtual Molinspiration screenings are in compliance with Ghose's rule.

Antidepressants: current strategies and future opportunities.

Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder. Current medication for the treatment of depression have limited efficacy and delayed onset of therapeutic action. In view of the limitation of the current antidepressant pharmaceuticals, tremendous research efforts are ongoing to search for a pharmacological treatment which may improve antidepressive efficacy, onset of action or even both therapeutic parameters. To address these needs, numerous combination therapies that maintain the benefits associated with selective serotonin reuptake inhibitors (SSRIs) but attempts to improve efficacy or reduce side effects by additional mechanism (5-HT1A, 5-HT2C) and newer approaches targeting excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory aminoacid system (GABA) or peptidergic system(neurokinin1, corticotrophin releasing factor1, melanin concentrating hormone1) have been identified. The goal of this review is to give a brief overview of the major advances in monoamine based treatment strategies and the new emerging approaches in the treatment of depression.