Transition metal ions exhibit a unique role in diverse biological activities of proteins by acting as cofactors. In particular, zinc and copper ions modulate enzymes activities as well as many catalytic and oxidative/reductive processes. The kinetics and mechanism of the substitution reactions of dichloro [ZnCl₂(terpy)] and [CuCl₂(terpy)]  (terpy = 2,2′:6′,2′′-terpyridine) with biologically relevant ligands have been studied as a function of nucleophile concentrations at pH 7.38, under pseudo-first-order condition by UV-Vis spectrophotometric techniques. The interactions of Cu(II) and Zn(II) complexes with tripeptide glutathione (GSH) were investigated under pseudo-first-order conditions with respect to the complex concentration. For the substitution process of Zn(II) complex with glutathione (GSH), pre-equilibrium and chelate formation have been noted. The [CuCl₂(terpy)] is more reactive than [ZnCl₂(terpy)] complex and the second-order rate constants for the first step follow the order of reactivity: GSH > DL-Asp > L -Met > 5’-GMP ~ 5’-IMP for Cu(II)  complex,  while for Zn(II) the order of reactivity is: DL-Asp >  L -Met > GSH ~  5’-GMP > 5’-IMP. The results are discussed in terms of mechanisms of interactions between metalloproteins and biomolecules.

Zinc(ll) and copper(II) complexes with organic molecules are used in clinical medicine, e.g. (i) complex of zinc(ll) acetate with erythromycin is used for ache therapy, (ii) copper chelating agents were developed to treat Wilson disease, an autosomal recessive genetic disorder that causes copper accumulation primarily in the liver. In general, organic ligands can contribute to better transport of metal ions through the lipophillic regions of cell membranes. However, it is also possible that some metal complexes are not able to reach their site of action in sufficient concentration due to their decreased solubility. Antibacterial activity of model  [ZnCl₂(terpy)]  and  [CuCl₂(terpy)] complexes  was tested against seven strains of bacteria. The complexes were more effective against Gram-positive than Gram-negative bacteria. Between complexes, stronger effect was observed for [CuCl₂(terpy)] complex. The best effect was exhibited against Sarcina lutea (5 mg/ml). Escherichia coli showed low sensitivity to both complexes. Results of the study of the antibacterial activity suggest an absence of permeability of the complexes through the membrane proteins.  

Between the functionalized chromones, 3-formylchromone is a highly reactive synthon used in many reactions due to the presence of electron-deficient centers at C-2, C-4 and the C-3 formyl group. Reaction of the -CHO group with nitrogen nucleophiles such as hydrazine and aminopyrazole derivatives has led to the formation of a variety of molecules that have been studied in detail for being of interest to drug discovery. Chromone-3-carboxaldehydes react with aromatic primary hydrazines mainly at the formyl group by a straightforward 1,2-addition to form the corresponding hydrazone, but when the reaction is submitted to prolonged heating, a pyrazole-type structure is produced by a 1,4-addition reaction accompanied by pyrone ring-opening followed by recyclization and proton transfer. On the other hand, reaction of 3-formylchromone with equimolar quantities of aminopyrazole derivatives was shown to afford mainly pyrazolo[1,5-a]-pyrimidines, formed by the above-mentioned cyclization process of an imine intermediate.

Led by the biological and pharmacological relevance of the 3-formylchromone derivatives and its interesting chemistry, in this work we present the synthesis of a series of pyrazoles (4a-c), hydrazones (5a-c), pyrazolo[1,5-a]-pyrimidines (6a, 6b) and one pyrazolo[3,4-b]-pyridine (7) and the report on their in vitro anti-leishmanial and anti-trypanosomal activity. Chemical results showed that the formation of regioisomer 7 may arise from an imine intermediary that undergoes 1,4-addition at C-2 by attack of C-4' from the pyrazole instead of the nitrogen atom N-2'. To the best of our knowledge, this is the first report regarding formation of pyrazolo[3,4-b]-pyridines by intramolecular attack of an sp² carbon atom.

The in vitro studies were performed against strains of Leishmania mexicana (bel 21) and Tripanosoma cruzi (DM28). Compounds 5a and 5b showed activity at micromolar level and good selectivity index (SI) with IC₅₀ values of 6.3 (SI = 3.4) and 15 (SI = 1.9) mM for L. Mexicana and 4.1 (SI = 5.2) and 10 (SI = 3) mM for T. cruzi respectively. From the above-mentioned results, compounds 5a and 5b may be considered for further chemical modifications in order to increase their activity as potential antiparasitic agents.

Since the beginning of mankind, plants have been used as the source of medicinal agents thereby becoming a major course to discovering new drugs. The practice of using traditional medicine is prevalent in Pakistan that has a rich history of herbal plants being used by Hakims in folk medicine (Unani medicine). The Asteraceae family is the largest plant family in Pakistan, with plants of considerable medicinal importance. Endophytes include all organisms that symptomless colonize the living internal tissues of their hosts during a variable period of their lifetime. There they produce a broad variety of bioactive secondary metabolites with unique structure that are advantageous for the plant. Endophytic actinomycetes also colonize the internal tissues of plants without causing any visible changes or damage. They exploit an unusual habitat and considering this, this may enable them to possess the potential to produce bioactive compounds as similar to their host plant. Our study explores the bioprospecting potential related to endophytic actinomycetes of Asteraceae medicinal plants of Pakistan. After isolation and identification the endophytes were screened for their bioactive metabolites potential for new drug targets. This included extensive biological and chemical screening. The bioactive compounds were purified by column chromatography and final identification was done through HPLC-MS and NMR. The purified compounds were observed to be extremely potent with promising antimicrobial potential against major pathogens including algae and fungal strains as well as posessing antioxidant and cytotoxic potential.       

Pentacyclic triterpenes represent a very promising and expansive platform for bioactive natural products. Its potential has begun to be exploited by the pharmaceutical industry. The study of these secondary metabolites has been focused mainly in evaluating their activity as potential anti-viral and anti-cancer agents, and in most cases, the increase of the activity is closely related to the chemical modification of the hydroxyl or carboxyl group located at positions C-3 and/or C-28 of the molecule. At present, most of the research on the chemical modification of triterpenes involves the insertion of heterocyclic rings, either through covalent bonds or by ring fusion. 

Serjanic acid (1) is a natural pentacyclic triterpene found in the fruits of the plant Phytolacca icosandra (Phytolaccaceae). Despite the structural similarities of this compound with other bioactive triterpenes such as oleanolic, boswellic and moronic acids, there are almost no studies on the chemical modification of this acid. Due to this, and based on the biological and pharmacological potential that this compounds might have, in this study we carried out the synthesis, structural characterization and cytotoxic evaluation of six new indolo-triterpene derivatives (8 – 13) from the natural triterpenoid serjanic acid (1). The compounds were synthesized via indolization reactions between the ketones 2 and phenylhydrazines 3 – 7 and their structures elucidated by IR, ¹H-NMR, ¹³C-NMR and HR-MS techniques as: indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (8), 5-bromoindolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (9), 7-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (10), 4-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (11), 6-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (12) and 4,7-dichloro-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (13). All compounds were tested trough the brine shrimp lethality assay to determinate their potential as cytotoxic agents. LC₅₀ values of the new synthesized compounds were between 28.6 and 78.8 micromolar.