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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 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.

Despite the vast availability of antibiotics, bacterial infections remain a leading cause of death worldwide. In an effort to enhance the armamentarium against resistant bacterial strains, 1,2,3-triazole (5a–x) and sulfonate (7a–j) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis) and four Gram-negative bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, 5e (derived from carvacrol) and 5u (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against S. pneumoniae (IC50: 62.53 and 39.33 μg/mL), E. faecalis (IC50: 36.66 and 61.09 μg/mL), and E. coli (IC50: 15.28 and 22.57 μg/mL). Furthermore, 5e and 5u also demonstrated moderate efficacy against multidrug-resistant E. coli strains and were therefore selected for further biological studies. Compound 5e in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant E. coli MRA11 and MRC17 strains, whereas compound 5u was selective against E. coli MRA11 strain. Growth kinetic studies on S. pneumoniae and E. coli treated with 5e and 5u showed an extended lag phase. 5e and 5u did not show significant cytotoxicity up to 100 μg/mL concentration on human embryonic kidney (HEK293) cells. Transmission electron microscopic (TEM) analysis of bacterial cells (S. pneumoniae and E. coli) exposed to 5e and 5u clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in S. pneumoniae and E. coli strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of Galleria mellonella (an in vivo model for antimicrobial studies) with 5e and 5u did not cause an alteration in the hemocyte density, thereby indicating lack of an immune response, and were nontoxic up to a concentration of 2.5 mg/mL.

Owing to the rise in antimicrobial and chemotherapeutic drug resistance, there is a desperate need to formulate newer as well as more effective agents. With this perspective, here we outline the synthesis of two novel gemini surfactants with different substitutions at the nitrogen atom of the benzimidazolium ring. Both the compounds induced significant reductions in Candida growth in various yeast strains. The reduction in Candida growth seemed likely through the reduction in ergosterol biosynthesis: a sterol constituent of yeast cell membranes. Different concentrations of both compounds were used to determine the cellular ergosterol content which indicates an important disordering of the ergosterol biosynthetic pathway. Cytotoxic studies were carried out using HEK 293 (human embryonic-kidney cells) and Galleria mellonella larvae (an in vivo model of antimicrobial studies). Administration of both the compounds to G. mellonella larvae diseased by the yeast Candida albicans resulted in increased survival indicating their in vivo activity.

Despite the fact that many small molecule inhibitors have been approved for cancer therapy, we still have a mighty long road to traverse in the field of targeted therapy against cancer. In order to overcome the challenges of chemo resistance and selectivity, we designed and synthesized 1,2,3-triazole appended indole-chalcone derivatives (4 a-q) and evaluated their antioxidant, anticancer and DNA binding properties. Among all the analogs, compounds with o-chloro (4b), o-fluoro (4h) and p-fluoro (4j) substitution exhibited potent antioxidant activity and the potency of 4 b was comparable to the standard ascorbic acid. In a cell based screen, compound 4 b inhibited the growth of human cervical cancer (SiHa) and colorectal epithelial carcinoma (SW620) cancer cell lines with an IC 50 values of 67.99 and 48.96 mg mL À1 , respectively without showing any significant cytotoxicity in human embryonic kidney cells (HEK293) at the similar concentration. To gain insight into the DNA-binding ability, various spectroscopic techniques such as UV-visible, fluorescence, circular dichroism, viscosity and cyclic voltametric studies were performed. These studies exposed that compounds 4 b, 4 h and 4 j act via noncovalent intercalative mode of binding to DNA causing their antiproliferative activity, supported by molecular docking studies. Our study revealed the non-toxic nature and potent activity of compound 4 b makes it a suitable candidate for further optimization and pharmacological studies.

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The present work involves a pharmacophore hybridization strategy to combine key biologically active scaffolds. The study led to the synthesis of quinoline based oxadiazole‐triazole conjugates with favorable physicochemical properties as anti‐cancer agents. Among the synthesized compounds 8(a–p), in vitro screening against a panel of four cancer cell lines identified compound 8k, with o‐chloro substitution on the phenyl ring, as potent against human lung carcinoma (A‐549) cells (IC50 =5.6 μM), while showing no significant cytotoxicity upto 200 μM concentration in normal cells. Compound 8 k with o‐chloro substitution induced nuclear morphological changes in A‐549 cells as visualized by DAPI (4,6‐diamidino‐2‐phenylindole) and was shown to bind firmly with A−T rich region in DNA. Changes in DNA topology studied through gel electrophoresis and groove mode of binding to ct‐DNA through multi‐spectroscopic techniques were observed, further validated by molecular docking studies. Overall, the study illustrates successful hybridization strategy leading to compound 8 k as promising anticancer agent for further structural optimization and biological evaluation.