Medicinal Chemistry - Volume 14, Issue 3, 2018

Background: Tuberculosis (TB) is a deadly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately, 1.8 and 1.3 million people are infected and die, from TB each year as estimated by the World Health Organization. Due to increase in the incidence of drug-resistant strains of Mtb, there is an urgent need to accelerate research which focuses on the development of new drugs with novel mechanism of action that can treat both drugsensitive and resistant TB infections. Objective: The purpose of this review study was to describe vitamins as drug target that can be explored to develop new anti tubercular drugs that can treat both drug-sensitive and resistant TB infections. Method: The methodological approaches include literature review which is performed in the databases like PubMed, Web of Science, Scopus, Springer and Science Direct, etc. On the basis of evaluation of literature sources, the review was complied. Results: This review study demonstrated that vitamins biosynthesis pathway could be used in the development of novel drug targets. Further sequencing of the Mtb genome facilitated research in target identification and validation that make possible the discovery of novel anti-TB agent with new mechanisms of action. Several compounds were identified, which target vitamin biosynthesis pathway /enzymes. Some other new targets were also identified and can be explored for the identification of novel structural moiety. Conclusion: Further exploration of these compounds which have been identified to target these vitamins related novel target pathways /molecules could led to the development of antitubercular drug which can be used in the treatment of drug sensitive and resistant TB.

Background: Seasonal and circadian changes are two factors described to affect blood levels of some biological molecules. The Total Antioxidant Capacity (TAC) is one global measure of the antioxidant capacity of a system. There is no agreement about the existence of day/night changes in TAC levels as well as there is no information about seasonal changes in TAC levels. Objective: The aims of this research are studying if there are summer/winter changes in TAC concentrations or if TAC concentrations have day/night changes. Method: Ninety-eight healthy subjects took part in the summer study of whom 64 participated in the winter one. Blood was sampled at 09:00, 12:00 and 00:00 h. TAC was measured by the ABTS radical cation technique. Results are expressed in mmol/L of trolox equivalents. Results: The subjects had significantly higher TAC levels in summer than winter at the three-time point studied. Summer 09:00 TAC concentration was significantly higher than the 12:00 and 00:00 h concentrations (1.34±0.26 vs 0.83±0.19, 0.75±0.18). Summer TAC 12:00 h concentrations were significantly higher than the 00:00 h concentrations (0.83±0.19 vs. 0.75±0.18). Winter 09:00 TAC concentrations were significantly higher than the 12:00 and 00:00 h concentrations (1.24±0.16 vs. 0.73±0.10, 0.67±0.13). There were no significant differences between the 12:00 and 00:00 h TAC concentrations. Conclusion: Strong methodological biases may be made if the seasonal and circadian changes in serum TAC concentration are not taken into account when researching in this area.

Background: 1,2,3-Triazole and its derivatives have important biological activities such as antimicrobial, anti-allergic, analgesic, anti-HIV, antiinflammatory, anticancer, antimalarial and antituberculosis. Other significant triazole derivatives are 1,2,4-triazoles which play a very important role in the medicinal chemistry due to the antiinflammatory, antimicrobial, antimigraine, anticancer, antimicrobial and antimycotic activities. In this study, we aimed to synthesize a new series of bis-1,2,3-triazole derivatives including 1,2,4-triazole to obtain more effective biological activities. Methods: In this study, a new series of bis-1,2,3-triazole compounds (9,10,11) were synthesized. Antimicrobial Activity: Disc diffusion method was used. Enzyme Inhibition: α-Glucosidase Inhibition was investigated. Antioxidant Activities: DPPH Radical Scavenging, Phosphomolybdenum- Reducing Antioxidant Power (PRAP) and Ferrous Ion-Chelating methods were used. Results: Compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f showed significant antibacterial and antifungal activity against all the strains tested. Compound 9g exhibited the highest AChE inhibition. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme. Compound 10f has the highest antioxidant activities. Conclusion: The compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f exhibit the best antimicrobial activity against the bacteria and fungi C.albicans, Y. enterocolitica, E. coli, Candida albicans, Yersinia enterocolitica. Compound 9g exhibit the highest AChE inhibition with 72.67 ± 3.92% at 100 μg/mL. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme compared to galantamine. Many of the compounds exhibited significant α-glucosidase inhibition activities. Compound 10f has the highest antioxidant activities (DPPH, PRAP, ferrous ionchelating) with 27.71 ± 0.85%, 0.689 ± 0.005, 42.07 ± 2.48 at 100 μg/mL, respectively.

Background: Low molecular weight 1-Aryl-1H-1,2,3-triazoles are endowed with various types of biological activities, such as against cancer, HIV and bacteria. Despite the existence of six different classes of antiretroviral drugs in clinical use, HIV/AIDS continue to be an on growing public health problem. Objective: In the present study, we synthesized and evaluated thirty 1-Aryl-1H-1,2,3-triazoles against HIV replication. Method: The compounds were prepared by Huisgen 1,3-dipolar cycloaddition protocol catalyzed by Cu(I) between aryl azides and propargylic alcohol followed by further esterification and etherification from a nucleophilic substitution with acid chlorides or alkyl bromides in good yields. The compounds were submitted to the inhibition of HIV replication and evaluation of their cytotoxicity. Initially, the compounds were screened at 10 μM and the most active were further evaluated in order to obtain some pharmacological parameters. Results: Thirty molecules were evaluated, six were selected – because they inhibited more than 80% HIV replication. We further showed that two of these compounds are 8-times more potent, and less cytotoxic, than nevirapine, an antiretroviral drug in clinical use. Conclusion: We identified very simple triazoles with promissing antiretroviral activities that led to the development of new drugs against AIDS.

Background: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been a global health threat and leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. Objective: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. Method: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 IIIB replication in acutely infected C8166 cells in vitro. Results: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC50 and therapeutic index (TI) values of 1.79 μg/mL, and 98.2, respectively. Conclusion: It has been demonstrated that the positions of methyl on the phenyl ring and 14- formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay the foundation for further structural modification and application of matrines as HIV-1 inhibitors.

Background: Acinetobacter is a Gram-negative, catalase-positive, oxidase-negative, non-motile, and no fermenting bacteria. Objective: In this study, some of the electronic and molecular properties, such as the highest occupied molecular orbital energy (EHOMO), lowest unoccupied molecular orbital energy (ELUMO), the energy gap between EHOMO and ELUMO, Mulliken atomic charges, bond lengths, of molecules having impact on antibacterial activity against A. baumannii were studied. In addition, calculations of some QSAR descriptors such as global hardness, softness, electronegativity, chemical potential, global electrophilicity, nucleofugality, electrofugality were performed. Method: The descriptors having impact on antibacterial activity against A. baumannii have been investigated based on the usage of 29 compounds employing two statistical methods called Linear Regression and Artificial Neural Networks. Results: Artificial Neural Networks obtained accuracies in the range of 83-100% (for active/inactive classifications) and q2=0.63 for regression. Conclusion: Three ANN models were built using various types of descriptors with publicly available structurally diverse data set. QSAR methodologies used Artificial Neural Networks. The predictive ability of the models was tested with cross-validation procedure, giving a q2=0.62 for regression model and overall accuracy 70-95 % for classification models.

Background: Serious side effects such as gastric intestinal ulcer, bleeding etc. are associated with most of the antiinflammatory and analgesic drugs. So, there is a need to search novel, potent, and safer antiinflammatory and analgesic drug. Method: Based on “biology-oriented synthesis approach”, piperine alkaloid was isolated from Piper nigrum L. and some derivatives of piperine having azomethine, sulfamoyl, propanoyl, acetamoyl and heterocyclic oxadiazole were synthesized. The structures of synthetic derivatives were confirmed by using different spectroscopic techniques such as ¹H-, ¹³C-NMR, EI-MS, and IR. Melting points were also determined for all compounds. Piperine and its all the synthetic derivatives were subjected to comparative in vivo evaluation of analgesic and antiinflammatory activities at the oral dose of 6 mg/kg/day. Analgesic activity was evaluated by tail immersion, hot plate and acetic acid writhing methods. While, antiinflammatory activity was evaluated by carrageenan-induced paw inflammation. In silico studies of all synthetic compounds was also conducted on COX-2 and adenosine kinase enzymes. Results: A number of derivatives showed enhanced antiinflammatory and analgesic activities as compared to piperine and standard drug diclofenac. Conclusion: The newly identified molecules may serve as lead for the future research in connection of potent and safer antiinflammatory and analgesic drug candidate.

Background: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. Objective: In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. Methods: This time, we used only in silico prediction and in vitro approaches. Results: Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. Conclusion: From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.

Background: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain. Objectives: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity. Method: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF. Results: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)- enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100. Conclusion: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.

Background: Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. Objective: The goal of this work was to synthesize a series of 1,3-benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. Methods: In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. Results: Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 μg/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 μg/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 μg/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. Conclusion: Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored.

Background: Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versatile in the field of medicinal chemistry because of their different biological activities. Among them, the imidazo[2,1-b]thiazole is an attractive fused heterocyclic core that has been extensively studied. Objective: The aim of the current study was to study the therapeutic applications of imidazo[2,1- b]thiazole derivatives as antimicrobial agents for the treatment of genitourinary infections. Method: A traditional synthetic methodology was involved to obtain a small series of imidazothiazole derivatives. Results: Herein, we report the antimicrobial activity of the imidazo[2,1-b]thiazole or imidazo[2,1- b]thiazolidine derivatives against selected fungi, Gram-positive and Gram-negative bacteria. Moreover, experiments were carried out to investigate the interference towards the endogenous microbiota. Conclusion: The most interesting of the series are the thiocyano derivatives (19, 23) showing a good profile for the treatment of genitourinary infections: a spectrum of activity covering both bacteria and fungi together with a reduced impact versus critical lines of Lactobacillus exerting defense against pathogens.