Novel 1,2,4-Triazolo[1,5-a]pyridines and Their Fused Ring Systems Attenuate Oxidative Stress and Prolong Lifespan of Caenorhabiditis elegans Ramadan Ahmed Mekheimer,* ,†,§ Ahmed Amir Radwan Sayed, ‡,§ and Eltaib Ali Ahmed ∥ † Department of Chemistry, Faculty of Science for Girls, King Abdulaziz University, Jeddah, P.O. Box 50918, Jeddah 21533, Saudi Arabia ‡ Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, P.O. Box 80203, Jeddah 215089, Saudi Arabia § Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt ∥ Department of Chemistry, Faculty of Education, AlFashir University, AlFashir 125, Sudan ABSTRACT: In this paper we report the synthesis of some novel 1,2,4- triazolo[1,5-a]pyridine and azolotriazolopyridine ring systems. The products were screened for various types of activity like antibacterial, antifungal, and antioxidative activity. Compound 13 was found to pose an antioxidative activity. In addition, this compound was found to extend the life span of Caenorhabiditis elegans under standard laboratory conditions and reduces both heat and chemical induced oxidative stress in C. elegans in a dose-dependent manner. Furthermore, treatment of worms with compound 13 was found to significantly attenuate the formation of advanced glycation end products and malondialdehyde in a dose-dependent manner. 1. INTRODUCTION Aging is associated with increased incidence of a range of diseases, some of which are pathogenetically linked to elevated levels of reactive oxygen species (ROS). 1 The mitochondrial free radical theory of aging 2 proposes an association between ROS generated during mitochondrial respiration (mtROS, the principal source of ROS in cells), accumulation of oxidative damage in mitochondrial DNA (mtDNA), and occurrence of mutations in the mitochondrial genome. These molecular changes lead to damaged or misfolded proteins, mitochondrial dysfunction, decline of cellular and tissue functions, enhanced formation of advanced glycation end products (AGE), and shortened life span. ROS generated due to mitochondrial dysfunction are thought to further induce mtDNA mutations, thus contributing to a vicious cycle of aging. 3−5 The extent of ROS formation and oxidative damage to mtDNA is inversely correlated with longevity across species. 6 Moreover, several studies have demonstrated an association between oxidative stress, mtDNA mutations, AGE formation, and age-related organ dysfunction. 4−7 Antioxidants may play an important role in preventing free radical damage associated with aging by interfering directly in the generation of radicals or by scavenging them. Previously, Brown et al., 8 Bartholome et al., 9 and Zhang et al. 10 have been indicated that antioxidants like Epigallocatechin gallate and α-lipoic acid have the ability to attenuate oxidative stress and prolong life span of wild-type Caenorhabditis elegans (C. elegans) under both standard and induced stress conditions. Recently, Wilson et al. 11 have demonstrated that proanthocyanidin, a potent antioxidant, reduced oxidative stress and extend the life span of wild-type C. elegans. In 2012, Grü nz and his co- workers 12 have proved that myricetin, quercetin, kaempferol, and naringenin improved the antioxidant status of wild-type C. elegans, which results in life span extension. We designed a study to determine whether the new synthesized 1,2,4-triazol[1,5-a]pyridine derivatives can prolong lifespan in a whole organism. For these studies, we required an organism with relatively short lifespan that could be assayed reproducibly and robustly and for which the genetic and environmental factors affecting lifespan were well-defined. The experimental organism that could best accommodate these requirements was the nematode, C. elegans, which has become a popular model for studying aging and longevity due to its short 2−3-week lifespan, rapid generation time, and experimental flexibility. 13 1,2,4-Triazolo[1,5-a]pyridines constituted an important class of heterocyclic compounds, which are of considerable interest due to their uses as active ingredients in antihypertensive, bro- nchodilatory, antiinflammatory, analgesic, and positive ino- tropic agents. 14−16 Isoxazoles, pyrroles, and pyrazoles are well-known examples of heteroaromatic organic compounds associated with diverse biological and pharmacological properties. Isoxazoles constitute an important family of five-membered hetrocycles in view of their use in many natural products syntheses 17,18 and occurrence in pharmaceutical agents such as COX-2 inhibitor Bextra. 19 The pyrrole skeleton is of great importance to chemists as well as biologists, as it is found naturally in plants and in animal cell constituents. 20 Pyrazole derivatives are synthetic targets of utmost importance in the pharmaceutical industry Received: October 22, 2011 Published: April 17, 2012 Article pubs.acs.org/jmc © 2012 American Chemical Society 4169 dx.doi.org/10.1021/jm2014315 | J. Med. Chem. 2012, 55, 4169−4177