Mohammad Abid

Synthesis, characterisation, reactivity and in vitro antiamoebic activity of hydrazone based oxovanadium(IV), oxovanadium(V) and µ-bis(oxo)bis{oxovanadium(V)} complexes

Binuclear, mu-bis(oxo)bis{oxovanadium(V)} complexes [(VOL)2(mu-O)2](2 and 7)(where HL are the hydrazones Hacpy-nah I or Hacpy-fah II; acpy = 2-acetylpyridine, nah = nicotinic acid hydrazide and fah = 2-furoic acid hydrazide) were prepared by the reaction of [VO(acac)2] and the ligands in methanol followed by aerial oxidation. The paramagnetic intermediate complexes [VO(acac)(acpy-nah)](1) and [VO(acac)(acpy-fah)](6) have also been isolated. Treatment of [VO(acac)(acpy-nah)] and [VO(acac)(acpy-fah)] with aqueous H2O2 yields the oxoperoxovanadium(V) complexes [VO(O2)(acpy-nah)](3) and [VO(O2)(acpy-fah)](8). In the presence of catechol (H2cat) or benzohydroxamic acid (H2bha), 1 and 6 give the mixed chelate complexes [VO(cat)L](HL =I: 4, HL =II: 9) or [VO(bha)L](HL =I: 5, HL =II: 10). Complexes 4, 5, 9 and 10 slowly convert to the corresponding oxo-mu-oxo species 2 and 7 in DMF solution. Ascorbic acid enhances this conversion under aerobic conditions, possibly through reduction of these complexes with concomitant removal of coordinated catecholate or benzohydroxamate. Acidification of 7 with HCl dissolved in methanol afforded a hydroxo(oxo) complex. The crystal and molecular structure of 2.1.5H2O has been determined, and the structure of 7 re-determined, by single crystal X-ray diffraction. Both of these binuclear complexes contain the uncommon asymmetrical {VO(mu-O)}2 diamond core. The in vitro tests of the antiamoebic activity of ligands I and II and their binuclear complexes 2 and 7 against the protozoan parasite Entamoeba histolytica show that the ligands have no amoebicidal activity while their vanadium complexes 2 and 7 display more effective amoebicidal activity than the most commonly used drug metronidazole (IC50 values are 1.68 and 0.45 microM, respectively vs 1.81 microM for metronidazole). Complexes 2 and 7 catalyse the oxidation of styrene and ethyl benzene effectively. Oxidation of styrene, using H2O2 as an oxidant, gives styrene epoxide, 2-phenylacetaldehyde, benzaldehyde, benzoic acid and 1-phenyl-ethane-1,2-diol, while ethyl benzene yields benzyl alcohol, benzaldehyde and 1-phenyl-ethane-1,2-diol.

Synthesis and antiamoebic activity of metronidazole thiosemicarbazone analogues

Repeated treatment of Entamoeba histolytica infection with commonly used antiamoebic drugs results in not only increasing the toxicity potential but also leads to the development of clinical resistance. Thus new effective agents with less toxicity against amoebiasis are urgently required. With this view, metronidazole thiosemicarbazone analogues 1-11 were synthesized wherein thioamide moiety was substituted by different cyclic and aromatic amines. These compounds were screened against HM1:IMSS strain of E. histolytica parasite cultured in vitro and the sensitivity of the parasite to the metronidazole thiosemicarbazones was evaluated using the microdilution method. Eight compounds (1-4, 7-9 and 11) were found better inhibitors of E. histolytica growth since IC50 values elicited by these compounds were much lower than metronidazole with compound 4 showing the most promising antiamoebic activity (IC50=0.56 microM). The study suggests the beneficial potential of these leads that need to be further explored in order to discover and develop better and yet safer therapeutic agents for amoebiasis.

Synthesis, QSAR and anticandidal evaluation of 1,2,3-triazoles derived from naturally bioactive scaffolds

In the present study, we used eight natural precursors (1a-h) with most of them having promising antimicrobial activities and synthesised their novel 1,2,3-triazole derivatives (3a-h). In the reaction sequences, the precursor compounds (1a-h) were converted to their respective alkyne (2a-h) followed by addition of benzyl azide freshly prepared by the reaction of benzyl bromide with sodium azide using [3 + 2] azide-alkyne cycloaddition strategy. Structural elucidation of all the triazole derivatives was done using FT-IR, (1)H, (13)C NMR, mass and elemental analysis techniques. The single crystal X-ray diffraction for 3d was also recorded. The result of in vitro anticandidal activity performed against three different strains of Candida showed that compound 3e was found superior/comparable to fluconazole (FLC) with IC50 values of 0.044 μg/mL against Candida albicans (ATCC 90028), 12.022 μg/mL against Candida glabrata (ATCC 90030), and 3.60 μg/mL against Candida tropicalis (ATCC 750). Moreover, at their IC50 values, compounds 3e and 3h showed <5% hemolysis which indicates the non-toxic behaviour of these inhibitors. Cytotoxicity assay was also performed on VERO cell line and all the derivatives were found non-toxic up to the concentration of 10.0 μg/mL. The in silico technique of 3D-QSAR was applied to establish structure activity relationship of the synthesized compounds. The results reveal the molecular fragments that play an essential role in improving the anticandidal activity.

Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation

Abstract Novel monocyclic β-lactam derivatives bearing aryl, phenyl and heterocyclic rings were synthesized as possible antibacterial agents. Cyclization of imines (3h, 3t) with phenylacetic acid in the presence of phosphoryl chloride and triethyl amine did not afford the expected β-lactams. Instead, highly substituted 1,3-oxazin-4-ones (4h, 4t) were isolated as the only product and confirmed by single crystal X-ray analysis of 4t. The results of antibacterial activity showed that compound 4l exhibited considerable antibacterial activity with MIC and MBC values of 62.5 µg/mL against Klebsiella pneumoniae. Cytotoxicity assay on Chinese Hamster Ovary (CHO) cell line revealed non-cytotoxic behavior of compounds 4d, 4h, 4k and 4l up to 200 μg/mL conc. Molecular docking was performed for compound 4l with penicillin binding protein-5 to identify the nature of interactions. The results of both in silico and in vitro evaluation provide the basis for compound 4l to be carried as a potential lead molecule in the drug discovery pipeline against bacterial infections.

Effect of novel triazole–amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies

The increasing incidence of human candidiasis and the tendency of Candida species to become resistant to existing chemotherapies are well-recognized health problems. The present study demonstrates the successful synthesis of novel triazole-amino acid hybrids with potent in vitro and in vivo inhibitory activity against Candida species. Particularly, compounds 68 and 70 showed potent in vitro activity against fluconazole (FLC) resistant as well as sensitive clinical isolates of Candida albicans. Time kill curve analysis of lead inhibitors 68 and 70 showed their fungistatic nature. Secretion of hydrolytic enzymes, mainly proteinases and phospholipases, decreased considerably in the presence of 68 and 70 indicating their interference in fungal virulence. TEM analysis of Candida cells exposed to compounds 68 and 70 clearly showed morphological changes and intracellular damage as their possible mode of action. A preliminary mechanistic study carried out on the two most effective inhibitors (68 and 70) revealed the inhibition of ergosterol biosynthesis thereby causing the cells to lose their integrity and viability. The selected compounds did not show significant cytotoxicity up to a concentration of 200 μg mL-1 in the HEK293 cell line. An in silico analysis of 68 and 70 binding to a modeled C. albicans CYP51 showed critical H-bonding as well as hydrophobic interactions with the important active site residues indicating the basis of their anti-Candida role. Studies on the larvae of Galleria mellonella showed that the selected inhibitors (68 and 70) were non-toxic, did not provoke an immune response and significantly reduced Candida proliferation in vivo.

Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors

Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a–c, 1e–h, 1j, 1l, 2a–c, 3d, 5c and 5e) as potent against different bacterial strains. By using the MTT assay on human cell line (HepG2), the viability of cell proliferation was evaluated and nine compounds (1c, 1e, 1j, 1l, 2a,b, 3d, 5c and 5e) showed no cytotoxic effect at the concentration range of 50–450 μg ml−1. In the biochemical evaluation against methionine aminopeptidase (MetAPs) from Streptococcus pneumonia (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds displayed differential behaviour against these four enzymes. Moreover, compound 1g showed 84% inhibition of SpMetAP, while compound 3d selectively inhibited MtMetAP with 79% inhibition and little effect on HsMetAP at 100 μM concentration. At the same concentration, compound 5e exhibited 87% and 85% inhibition of EfMetAP and SpMetAP, respectively. Understanding the mode of binding through modeling at the active site provided the structural basis for the possible mode of inhibition. Together, these data will be useful for further development of diketo acid based inhibitors with improved potency and selectivity.

A structure guided drug-discovery approach towards identification of Plasmodium inhibitors

Rapidly increasing resistance to the currently available antimalarial drugs has drawn attention globally for the search for more potent novel drugs with a high therapeutic index. The genome sequencing of the human malarial parasite Plasmodium falciparum has provided extensive information to understand potential target pathways and efforts are being made to develop lead inhibitors with a hope to eliminate the disease. This review is focused on a brief description of key biochemical targets identified from the genome sequence of P. falciparum. This review also summarizes the work undertaken by different scientific groups over the last five years to develop inhibitors from natural, semisynthetic or synthetic sources, which will be valuable to medicinal chemists to develop novel antimalarial agents.

Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin

An elevated prothrombotic state is a major risk factor for venous thromboembolism, atrial fibrillation and cardiac strokes. The regulation of various coagulation cascade proteases plays an important role in determining a prothrombotic state. Clinically used anticoagulants are inhibitor of enzymes that are involved in the coagulation pathway, primarily thrombin and factor Xa. The conformational activation of antithrombin by heparin is a critical step in the inhibition of factor Xa by antithrombin. Despite heparin being the most potent physiological activator which enhances the otherwise very lethargic antithrombin inhibition of factor Xa by approximately 1,000-fold, the conventional heparin therapy poses serious complications because of heparin’s polyanionic nature and its cross-reactivity. A number of attempts have been carried out in designing alternative non-heparin based conformational activators of antithrombin for factor Xa inhibition. Studies have demonstrated appreciable activation of antithrombin by small organic molecules, but not much is known about the specificity and effects of these molecules on structure and stability. It is assumed that these activators of antithrombin perform their function by binding to heparin binding site. A recently identified cavity which links the heparin binding site to the strand 2A for antithrombin activation also seems to be an ideal target apart the heparin binding site of antithrombin. There are opportunities in discovering more activators from naturally available organic scaffolds and also for modifying such scaffolds for designing better conformational activators with minimum associated complications. This review summarizes the current literature on the mainstay anticoagulants and non-heparin based antithrombin conformation modulators.

Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action

Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP) induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.

Elucidating the specificity of non-heparin-based conformational activators of antithrombin for factor Xa inhibition.

Introduction: Antithrombin, the principal inhibitor of coagulation proteases, requires allosteric activation by its physiological cofactor, heparin or heparin sulfate to achieve physiologically permissible rates. This forms the basis of heparins use as a clinical anticoagulant. However, heparin therapy is beset with severe complications, giving rise to the need to search new non-heparin activators of antithrombin, devoid of these complications and with favorable safety profiles. Materials and Methods: We chose some representative organic compounds that have been shown to be involved in coagulation modulation by affecting antithrombin and applied a blind docking protocol to find the binding energy and interactions of the modified (sulfated) versus unmodified organic scaffolds. Results and Conclusion: Increased sulfation plays a key role in shifting the specificity of organic compounds like quercetin, diosmin, rutin, mangiferin, isomangostin, Trapezifolixanthone and benzofuran towards the heparin binding site (HBS). However, in hesperetin and tetrahydroisoquinoline, sulfation shifts the specificity away from HBS. We have further tried to elucidate changes in the binding affinity of quercetin on account of gradual increase in the number of hydroxyl groups being substituted by sulfate groups. The results show gradual increase in binding energy with increase in sulfation. A theoretical screening approach is an ideal mechanism to predict lead molecules as activators of antithrombin and in determining the specificity for antithrombin.