Synthesis of 2,4,6-trisubstituted pyrimidines as antimalarial agents

A series of 2,4,6-trisubstituted-pyrimidines were synthesized and evaluated for their in vitro antimalarial activity against Plasmodium falciparum. Of the 18 compounds synthesized, 14 compounds have shown MIC in the range of 0.25-2 microg/mL. These compounds are in vitro severalfold more active than pyrimethamine.     

Syntheses of 2,4,6-trisubstituted triazines as antimalarial agents

A series of 2,4,6-trisubstituted-1,3,5-triazines (2a-s) were synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. Out of the 19 compounds synthesized eight compounds showed MIC in the range of 1-2 microg/mL. These compounds are in vitro several times more active than cycloguanil.     

Novel coumarin derivatives as potential antidyslipidemic agents

A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.     

Nitrone derivatives of trolox as neuroprotective agents

Synthesis of nitrone derivatives of trolox is described. Their biological evaluation was performed in vitro for scavenging different free radicals, inhibiting Fe(2+)-induced lipid peroxidation, and in vivo in a permanent middle cerebral artery occlusion model in mice. New compounds exert pharmacological activities comparable to or better than those of trolox or nitrone-type reference compounds.     

A small library of trisubstituted pyrimidines as antimalarial and antitubercular agents

A small library of 20 trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial and antitubercular activities. Out of the total screened compounds, 16 compounds have shown in vitro antimalarial activity against Plasmodium falciparum in the range of 0.25-2microg/mL and 8 compounds have shown antitubercular activity against Mycobacterium tuberculosis H(37)Ra, at a concentration of 12.5microg/mL.     

Synthesis of substituted indole derivatives as a new class of antimalarial agents

A series of substituted indole derivatives were synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. Out of the 24 compounds synthesized six compounds have shown MIC of 1 microg/mL. These compounds are in vitro several folds more active than pyrimethamine.     

Chloropyrimidines as a new class of antimicrobial agents

In the course of our investigations of pyrimidines as antimycotic agents, we have identified a sub-class, with significant in vitro activity against mycobacteria. The salient feature of these pyrimidine derivatives (3a-o and 7a,b) is their appended aryl, heteroaryl and alkylthio substituent at position 6 and also alkylthio substituent at position 2. The rational design, synthesis, and evaluation of the in vitro antibacterial activity against six pathogenic bacteria including virulent and non-virulent strains of Mycobacterium tuberculosis is described. Some of the synthesized compounds (3c, 3h, 3i, 3o) have displayed only potent in vitro antimycobacterial activity with MIC of 0.75 microg/mL except 3i which also demonstrated activity against Escherichia coli at 12.5 microg/mL concentration. Only two compounds, 3a and 3b, demonstrated antibacterial activity against Pseudomonas aeruginosa and E. coli with MIC 12.5 microg/mL. All the synthesized compounds were also evaluated for their antimycotic activity against five pathogenic fungi but only some of them 3j-n and 7a,b were found most potent against Aspergillus fumigatus and Trichophyton mentagrophytes.     

Suitably functionalised pyrimidines as potential antimycotic agents

Various suitably functionalized pyrimidine derivatives have been synthesized to explore their potential as antimycotic agents. Some of the synthesized compounds 4c, 4d, 8a-e have shown highly significant in vitro antifungal activity against five human pathogenic fungi.     

Evaluation of coumarin derivatives as anti-fungal agents against soil-borne fungal pathogens

Development of new and safer pesticides that are target-specific is backed by a strong Federal, public and commercial mandate. In order to generate a new generation of pesticides that are more ecologically friendly and safe, natural products are being evaluated for pesticidal activities. Many plant-derived chemicals have proven pesticidal properties, including compounds like sesamol (3,4-Methylenedioxyphenol), a lipid from sesame oil and coumarins (1,2-Benzopyrone) found in a variety of plants such as clover, sweet woodruff and grasses. Both of these plant-derived compounds have been shown to inhibit a range of fungi and bacteria and it is believed that these cyclic compounds behave as natural pesticidal defense molecules for plants. These compounds represent a starting point for the exploration of new derivative compounds possessing a range of antifungal activity and for use as seed protectants. Within this study, six derivatives of coumarin that resembled sesamol's structure were screened for their antifungal activity against a range of soil-bome plant pathogenic fungi. Fungi in this in vitro screen included Macrophomina phaseolina (causal agent of charcoal rot) and Pythium spp. (causal agent of seedling blight), two phylogenetically diverse and economically important plant pathogens. Preliminary studies indicate that many of these novel coumarin derivatives work very effectively in vitro to inhibit fungal growth and several coumarin derivatives have higher antifungal activity and stability as compared to either the original coumarin or sesamol compounds alone. Interestingly, several of these highly active coumarin derivatives are halogenated compounds with solubility in water, and they are relatively easy and inexpensive to synthesize. These halogenated coumarin derivatives remained active for extended periods of time displaying 100% inhibition of fungal growth for greater than 3 weeks in vitro. In addition to the in vitro fungal inhibition assays, preliminary phytotoxicity assays of these halogenated coumarin compounds show no obvious plant toxicity issues or interference in plant development. These results support additional research in this area of natural pesticide development.     

9-Deoxopodophyllotoxin derivatives as anti-cancer agents.

Several 9-deoxo-9-substituted podophyllotoxin derivatives were synthesised starting from naturally occuring podophyllotoxin and their anti-cancer activity was evaluated against in vitro human cancer cell line assay. It was observed that these compounds do possess good anti-cancer activity particularly against ovarian, renal and lung cancer cell lines.     

(1,4-Benzothiazinyloxy)alkylpiperazine derivatives as potential antihypertensive agents

A series of compounds having a piperazine moiety variously linked to the benzothiazine nucleus were synthesized and evaluated for their in vitro alpha-adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a oxyalkyl-(2-methoxyphenyl)piperazine side chain were good alpha1-adrenoreceptor ligands.     

Benzohydroxamic acids as potent and selective anti-HCV agents

A diverse collection of 40 derivatives of benzohydroxamic acid (BHAs) of various structural groups were synthesized and tested against hepatitis C virus (HCV) in full-genome replicon assay. Some of these compounds demonstrated an exceptional activity, suppressing viral replication at sub-micromolar concentrations. The compounds were inactive against key viral enzymes NS3, and NS5B in vitro assays, suggesting host cell inhibition target(s). The testing results were consistent with metal coordination by the BHAs hydroxamic group in complex with a target(s). Remarkably, this class of compounds did not suppress poliomyelitis virus (PV) propagation in RD cells indicating a specific antiviral activity of BHAs against HCV.     

Alkyl-linked bis-THTT derivatives as potent in vitro trypanocidal agents

The effect of several alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) on Leishmania donovani, Trypanosoma brucei rhodesiense, and Plasmodium falciparum is reported. Most of the compounds exhibited a potent activity against the three parasitic strains but the best in vitro activity profiles were found against T. b. rhodesiense with IC(50) values ranging between 0.3 and 4 microM for the most active compounds.     

Solid support synthesis of 6-aryl-2-substituted pyrimidin-4-yl phenols as anti-infective agents

A library of 30 trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial and antitubercular activity. Out of the 30 compounds synthesized, 23 compounds have shown in vitro antimalarial activity against Plasmodium falciparum in the range of 0.25-2 microg/mL and 16 compounds have shown antitubercular activity against Mycobacterium tuberculosis H37Ra, at a concentration of 25 microg/mL.     

Synthesis of new S-derivatives of clubbed triazolyl thiazole as anti-Mycobacterium tuberculosis agents

In the present study, a series of N-{4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-2-substituted-amide (1a-d) derivatives were synthesized in good yields and characterized by IR, 1H NMR, mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhosa and then were screened for antitubercular activity against Mycobacterium tuberculosis H37 Rv strain by broth microdilution assay method. The antibacterial data of the tested compounds indicated that most of the synthesized compounds showed better activity against bacteria compared to reference drugs. The in vitro antitubercular activity reports of tested compounds against M. tuberculosis strain H37 Rv showed moderate to better activity.     

Synthesis and biological evaluation of novel pyrazolyl-2,4-thiazolidinediones as anti-inflammatory and neuroprotective agents

Novel pyrazolyl-2,4-thiazolidinediones were prepared via the reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinediones and substituted benzyl-2,4-thiazolidinediones. The resultant compounds were first evaluated for their anti-inflammatory and neuroprotective properties in vitro. The active compounds were further studied in vivo by using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays. We identified four novel compounds that showed protective effects in vitro at non-toxic concentrations, and were also effective in the animal models of acute and sub-acute inflammation.     

New imidazolidinedione derivatives as antimalarial agents

A series of new N-alky- and N-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and Rhesus monkey models. New compounds are generally metabolically stable, weakly active in vitro against Plasmodium falciparum clones (D6 and W2) and in mice infected with Plasmodium berghei sporozoites. Representative compounds 8e and 9c showed good causal prophylactic activity in Rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by IM, delayed patency for 19-21 days and 54-86 days, respectively, as compared to the untreated control. By oral, 9c showed only marginal activity in causal prophylactic and radical curative tests at 50 mg/kg/day×3 and 30 mg/kg/day×7 plus chloroquine 10 mg/kg for 7 days, respectively.     

Thymol and eugenol derivatives as potential antileishmanial agents

In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5–10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100 mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl-thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis.     

2-Hydroxyphenacyl azoles and related azolium derivatives as antifungal agents

2-Hydroxyphenacyl azole and 2-hydroxyphenacyl azolium compounds have been described as a new class of azole antifungals. Most target compounds showed significant in vitro antifungal activities against tested fungi (Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum) with low MICs values included in the range of 0.25-32 microg/mL comparable to reference drug fluconazole. The most active compounds were also assessed for their cytotoxicity using MTT colorimetric assay on normal mouse fibroblast (NIH/3T3) cells. The results of antifungal activity and toxicity tests indicated that these compounds display antifungal activity at non-cytotoxic concentrations.     

Novel 3-pyridinecarbonitriles incorporating sulfonamide moieties as anti-breast cancer agents

A novel series of 3-pyridinecarbonitrile derivatives incorporating sulfonamide moieties and sulfonyl derivatives was synthesized using 2-chloro-6-methylnicotinonitrile as a strategic starting material. The structures of the synthesized compounds were elucidated on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data. All the prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (MCF-7). Most of the compounds showed good to moderate activity, higher than that of the reference drug doxorubicin. Two compounds showed the same activity as doxorubicin, while three compounds exhibited remarkable activity.